CDK-Inhibitory pyrimidines, their production and use as pharmaceutical agents

ABSTRACT

This invention relates to pyrimidine derivatives of general formula I 
     
       
         
         
             
             
         
       
     
     in which R 1 , R 2 , X, A and B have the meanings that are contained in the description, as inhibitors of the cyclin-dependent kinases, their production as well as their use as medications for treating various diseases.

This invention relates to pyrimidine derivatives, their production as well as their use as medications for treating various diseases.

The CDKs (cyclin-dependent kinase) is an enzyme family that plays an important role in the regulation of the cell cycle and thus is an especially advantageous target for the development of small inhibitory molecules. Selective inhibitors of the CDKs can be used for treating cancer or other diseases that cause disruptions of cell proliferation.

Pyrimidines and analogs are already described as active ingredients, such as, for example, the 2-anilino-pyrimidines as fungicides (DE 4029650) or substituted pyrimidine derivatives for treating neurological or neurodegenerative diseases (WO 99/19305). As CDK-inhibitors, the most varied pyrimidine derivatives are described, for example bis(anilino)-pyrimidine derivatives (WO 00/12486), 2-amino-4-substituted pyrimidines (WO 01/14375), purines (WO 99/02162), 5-cyano-pyrimidines (WO 02/04429), anilinopyrimidines (WO 00/12486) and 2-hydroxy-3-N,N-dimethylaminopropoxy-pyrimidines (WO 00/39101).

The object of this invention is to provide compounds that have better properties than the inhibitors that are already known. The substances that are described here are more effective, since they already inhibit in the nanomolar range and can be distinguished from other already known CDK-inhibitors such as, e.g., olomoucine and roscovitine.

It has now been found that compounds of general formula I

in which

-   -   R¹ stands for hydrogen, halogen, C₁-C₆-alkyl, nitro, or for the         group —COR⁵, —OCF₃, —(CH₂)_(n)R⁵, —S—CF₃ or —SO₂CF₃,     -   R² stands for C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkinyl, or         C₃-C₁₀-cycloalkyl or for C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl,         C₂-C₁₀-alkinyl, or C₃-C₁₀-cycloalkyl that is substituted in one         or more places in the same way or differently with hydroxy,         halogen, C₁-C₆-alkoxy, C₁-C₆-alkylthio, amino, cyano,         C₁-C₆-alkyl, —NH—(CH₂)_(n)—C₃-C₁₀-cycloalkyl, C₃-C₁₀-cycloalkyl,         C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, C₂-C₆-alkinyl,         C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkoxy-C₁-C₆-alkyl,         —NHC₁-C₆-alkyl, —N(C₁-C₆-alkyl)₂, —SO(C₁-C₆-alkyl),         —SO₂(C₁-C₆-alkyl), C₁-C₆-alkanoyl, —CONR³R⁴, —COR⁵,         C₁-C₆-alkylOAc, carboxy, aryl, heteroaryl, —(CH₂)_(n)-aryl,         —(CH₂)_(n)-heteroaryl, phenyl-(CH₂)_(n)-R⁵, —(CH₂)_(n)PO₃(R⁵)₂         or with the group —R⁶ or —NR³R⁴, and the phenyl,         C₃-C₁₀-cycloalkyl, aryl, heteroaryl, —(CH₂)_(n)-aryl and         —(CH₂)_(n)-heteroaryl itself optionally can be substituted in         one or more places in the same way or differently with halogen,         hydroxy, C₁-C₆-alkyl, C₁-C₆-alkoxy, heteroaryl, benzoxy or with         the group —CF₃ or —OCF₃, and the ring of the C₃-C₁₀-cycloalkyl         and the C₁-C₁₀-alkyl optionally can be interrupted by one or         more nitrogen, oxygen and/or sulfur atoms and/or can be         interrupted by one or more ═C═O groups in the ring and/or         optionally one or more possible double bonds can be contained in         the ring, or     -   R² stands for the group

-   -   X stands for oxygen or for the group —NH—, —N(C₁-C₃-alkyl) or         for —OC₃-C₁₀-cycloalkyl, which can be substituted in one or more         places in the same way or differently with a heteroaromatic         compound, or     -   X and R² together form a C₃-C₁₀-cycloalkyl ring, which         optionally can contain one or more heteroatoms and optionally         can be substituted in one or more places with hydroxy,         C₁-C₆-alkyl, C₁-C₆-alkoxy or halogen,     -   A and B, in each case independently of one another, stand for         hydrogen, hydroxy, C₁-C₃-alkyl, C₁-C₆-alkoxy or for the group         —SR⁷, —S(O)R⁷, —SO₂R⁷, —NHSO₂R⁷, —CH(OH)R⁷, —CR⁷(OH)—R⁷,         C₁-C₆-alkylP(O)OR³OR⁴ or —COR⁷, or for

or

-   -   A and B together form a C₃-C₁₀-cycloalkyl ring that optionally         can be interrupted by one or more nitrogen, oxygen and/or sulfur         atoms and/or can be interrupted by one or more ═C═O or ═SO₂         groups in the ring and/or optionally one or more possible double         bonds can be contained in the ring, and the C₃-C₁₀-cycloalkyl         ring optionally can be substituted in one or more places in the         same way or differently with hydroxy, halogen, C₁-C₆-alkoxy,         C₁-C₆-alkylthio, amino, cyano, C₁-C₆-alkyl, C₂-C₆-alkenyl,         C₃-C₁₀-cycloalkyl, C₁-C₆-alkoxy-C₁-C₆-alkyl, —NHC₁-C₆-alkyl,         —N(C₁-C₆-alkyl)₂, —SO(C₁-C₆-alkyl), —SO₂R⁷, C₁-C₆-alkanoyl,         —CONR³R⁴, —COR⁵, C₁-C₆-alkoxyOAc, phenyl or with the group R⁶,         whereby the phenyl itself optionally can be substituted in one         or more places in the same way or differently with halogen,         hydroxy, C₁-C₆-alkyl, C₁-C₆-alkoxy or with the group —CF₃ or         —OCF₃,     -   R³ and R⁴, in each case independently of one another, stand for         hydrogen, phenyl, benzyloxy, C₁-C₁₂-alkyl, C₁-C₆-alkoxy,         C₂-C₄-alkenyloxy, C₃-C₆-cycloalkyl, hydroxy,         hydroxy-C₁-C₆-alkyl, dihydroxy-C₁-C₆-alkyl, heteroaryl,         heterocyclo-C₃-C₁₀-alkyl, heteroaryl-C₁-C₃-alkyl,         C₃-C₆-cycloalkyl-C₁-C₃-alkyl that is optionally substituted with         cyano, or for         -   C₁-C₆-alkyl that is optionally substituted in one or more             places in the same way or differently with phenyl, pyridyl,             phenyloxy, C₃-C₆-cycloalkyl, C₁-C₆-alkyl or C₁-C₆-alkoxy,         -   whereby the phenyl itself can be substituted in one or more             places in the same way or differently with halogen,             C₁-C₆-alkyl, C₁-C₆-alkoxy or with the group —SO₂NR³R⁴,         -   or for the group —(CH₂)_(n)NR³R⁴, —CNHNH₂ or —NR³R⁴, or     -   R³ and R⁴ together form a C₃-C₁₀-cycloalkyl ring that optionally         can be interrupted by one or more nitrogen, oxygen and/or sulfur         atoms and/or can be interrupted by one or more ═C═O groups in         the ring and/or optionally one or more possible double bonds can         be contained in the ring,     -   R⁵ stands for hydroxy, phenyl, C₁-C₆-alkyl, C₃-C₆-cycloalkyl,         benzoxy, C₁-C₆-alkylthio or C₁-C₆-alkoxy,     -   R⁶ stands for a heteroaryl or C₃-C₁₀-cycloalkyl ring, whereby         the ring has the above-indicated meaning,     -   R⁷ stands for halogen, hydroxy, phenyl, C₁-C₆-alkyl,         C₂-C₆-alkenyl, C₂-C₆-alkinyl, C₃-C₁₀-cycloalkyl, with the         above-indicated meaning, or for the group —NR³R⁴, or for a         C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkinyl or C₃-C₇-cycloalkyl         that is substituted in one or more places in the same way or         differently with hydroxy, C₁-C₆-alkoxy, halogen, phenyl, —NR³R⁴         or phenyl, which itself can be substituted in one or more places         in the same way or differently with halogen, hydroxy,         C₁-C₆-alkyl, C₁-C₆-alkoxy, halo-C₁-C₆-alkyl, halo-C₁-C₆-alkoxy,         or R⁷ stands for phenyl, which itself can be substituted in one         or more places in the same way or differently with halogen,         hydroxy, C₁-C₆-alkyl or C₁-C₆-alkoxy, halo-C₁-C₆-alkyl, or         halo-C₁-C₆-alkoxy,     -   R⁸, R⁹ and     -   R¹⁰, in each case independently of one another, stand for         hydrogen, hydroxy, C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkinyl,         C₃-C₁₀-cycloalkyl, aryl, heteroaryl or for C₁-C₁₀-alkyl,         C₂-C₁₀-alkenyl, C₂-C₁₀-alkinyl or C₃-C₁₀-cycloalkyl that is         optionally substituted in one or more places in the same way or         differently with hydroxy, halogen, C₁-C₆-alkoxy,         C₁-C₆-alkylthio, amino, cyano, C₁-C₆-alkyl,         —NH—(CH₂)_(n)-C₃-C₁₀-cycloalkyl, C₃-C₁₀-cycloalkyl,         C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, C₂-C₆-alkinyl,         C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkoxy-C₁-C₆-alkyl,         —NHC₁-C₆-alkyl, —N(C₁-C₆-alkyl)₂, —SO(C₁-C₆-alkyl),         —SO₂(C₁-C₆-alkyl), C₁-C₆-alkanoyl, —CONR³R⁴, —COR⁵,         C₁-C₆-alkylOAc, carboxy, aryl, heteroaryl, —(CH₂)_(n)-aryl,         —(CH₂)_(n)-heteroaryl, phenyl-(CH₂)_(n)—R⁵, —(CH₂)_(n)PO₃(R⁵)₂         or with the group —R⁶ or —NR³R⁴, and the phenyl,         C₃-C₁₀-cycloalkyl, aryl, heteroaryl, —(CH₂)_(n)-aryl and         —(CH₂)_(n)-heteroaryl itself optionally can be substituted in         one or more places in the same way or differently with halogen,         hydroxy, C₁-C₆-alkyl, C₁-C₆-alkoxy or with the group —CF₃ or         —OCF₃, and the ring of C₃-C₁₀-cycloalkyl and the C₁-C₁₀-alkyl         optionally can be interrupted by one or more nitrogen, oxygen         and/or sulfur atoms and/or can be interrupted by one or more         ═C═O groups in the ring and/or optionally one or more possible         double bonds can be contained in the ring, and     -   n stands for 0-6,         as well as isomers, diastereomers, enantiomers and salts thereof         that overcome known drawbacks.

Alkyl is defined in each case as a straight-chain or branched alkyl radical, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, heptyl, octyl, nonyl and decyl.

Alkoxy is defined in each case as a straight-chain or branched alkoxy radical, such as, for example, methyloxy, ethyloxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy, pentyloxy, isopentyloxy, or hexyloxy.

Alkylthio is defined in each case as a straight-chain or branched alkylthio radical, such as, for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, isopentylthio or hexylthio.

Cycloalkyl is defined in general as monocyclic alkyl rings, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, but also bicyclic rings or tricyclic rings such as, for example, norbornyl, adamantanyl, etc.

The ring systems, in which optionally one or more possible double bonds can be contained in the ring, are defined as, for example, cycloalkenyls, such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, or cycloheptenyl, whereby the linkage can be carried out both to the double bond and to the single bonds.

If A and B, R³ and R⁴, X and R², in each case independently of one another, together form a C₃-C₁₀-cycloalkyl ring, which optionally can be interrupted by one or more heteroatoms, such as nitrogen atoms, oxygen atoms and/or sulfur atoms, and/or can be interrupted by one or more ═C═O groups in the ring and/or optionally one or more possible double bonds can be contained in the ring, however, the above-mentioned definitions are also intended to include heteroaryl radical or heterocycloalkyl and heterocycloalkenyl.

Halogen is defined in each case as fluorine, chlorine, bromine or iodine.

The alkenyl substituents in each case are straight-chain or branched, whereby, for example, the following radicals are meant: vinyl, propen-1-yl, propen-2-yl, but-1-en-1-yl, but-1-en-2-yl, but-2-en-1-yl, but-2-en-2-yl, 2-methyl-prop-2-en-1-yl, 2-methyl-prop-1-en-1-yl, but-1-en-3-yl, ethinyl, prop-1-in-1-yl, but-1-in-1-yl, but-2-in-1-yl, but-3-en-1-yl, and allyl.

Alkinyl is defined in each case as a straight-chain or branched alkinyl radical that contains 2-6, preferably 2-4 C atoms. For example, the following radicals can be mentioned: acetylene, propin-1-yl, propin-3-yl, but-1-in-1-yl, but-1-in-4-yl, but-2-in-1-yl, but-1-in-3-yl, etc.

The aryl radical in each case comprises 3-12 carbon atoms and in each case can be benzocondensed.

For example, there can be mentioned: cyclopropenyl, cyclopentadienyl, phenyl, tropyl, cyclooctadienyl, indenyl, naphthyl, azulenyl, biphenyl, fluorenyl, anthracenyl, etc.

The heteroaryl radical in each case comprises 3-16 ring atoms, and instead of the carbon can contain one or more heteroatoms that are the same or different, such as oxygen, nitrogen or sulfur, in the ring, and can be monocyclic, bicyclic, or tricyclic and in addition in each case can be benzocondensed.

For example, there can be mentioned:

Thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, etc. and benzo derivatives thereof, such as, e.g., benzofuranyl, benzothienyl, benzoxazolyl, benzimidazolyl, indazolyl, indolyl, isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc. and benzo derivatives thereof, such as, e.g., quinolyl, isoquinolyl, etc., or azocinyl, indolizinyl, purinyl, etc. and benzo derivatives thereof; or quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl, oxepinyl, etc.

Heterocycloalkyl stands for an alkyl ring that comprises 3-12 carbon atoms, which instead of the carbon contains one or more heteroatoms that are the same or different, such as, e.g., oxygen, sulfur or nitrogen.

As heterocycloalkyls, there can be mentioned, e.g.: oxiranyl, oxethanyl, aziridinyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, dioxolanyl, imidazolidinyl, pyrazolidinyl, dioxanyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, quinuclidinyl, etc.

Heterocycloalkenyl stands for an alkyl ring that comprises 3-12 carbon atoms, which instead of the carbon contains one or more heteroatoms that are the same or different such as, e.g., oxygen, sulfur or nitrogen, and which is partially saturated.

As heterocycloalkenyls, there can be mentioned, e.g.: pyran, thiin, dihydroacet, etc.

If an acid group is included, the physiologically compatible salts of organic and inorganic bases are suitable as salts, such as, for example, the readily soluble alkali and alkaline-earth salts, as well as N-methyl-glucamine, dimethyl-glucamine, ethyl-glucamine, lysine, 1,6-hexadiamine, ethanolamine, glucosamine, sarcosine, serinol, tris-hydroxy-methyl-amino-methane, aminopropane diol, Sovak base, and 1-amino-2,3,4-butanetriol.

If a basic group is included, the physiologically compatible salts of organic and inorganic acids are suitable, such as hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, tartaric acid, i.a.

Those compounds of general formula (I) in which

-   -   R¹ stands for hydrogen, halogen, C₁-C₆-alkyl, nitro, or for the         group —COR⁵, —OCF₃, —(CH₂)_(n)R⁵, —S—CF₃ or —SO₂CF₃,     -   R² stands for C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkinyl, or         C₃-C₁₀-cycloalkyl or for C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl,         C₂-C₁₀-alkinyl, or C₃-C₁₀-cycloalkyl that is substituted in one         or more places in the same way or differently with hydroxy,         halogen, C₁-C₆-alkoxy, C₁-C₆-alkylthio, amino, cyano,         C₁-C₆-alkyl, —NH—(CH₂)_(n)—C₃-C₁₀-cycloalkyl, C₃-C₁₀-cycloalkyl,         C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, C₂-C₆-alkinyl,         C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkoxy-C₁-C₆-alkyl,         —NHC₁-C₆-alkyl, —N(C₁-C₆-alkyl)₂, —SO(C₁-C₆-alkyl),         —SO₂(C₁-C₆-alkyl), C₁-C₆-alkanoyl, —CONR³R⁴, —COR⁵,         C₁-C₆-alkylOAc, carboxy, aryl, heteroaryl, —(CH₂)_(n)-aryl,         —(CH₂)_(n)-heteroaryl, phenyl-(CH₂)_(n)—R⁵, —(CH₂)_(n)PO₃(R⁵)₂         or with the group —R⁶ or —NR³R⁴, and the phenyl,         C₃-C₁₀-cycloalkyl, aryl, heteroaryl, —(CH₂)_(n)-aryl and         —(CH₂)_(n)-heteroaryl itself optionally can be substituted in         one or more places in the same way or differently with halogen,         hydroxy, C₁-C₆-alkyl, C₁-C₆ alkoxy, heteroaryl, benzoxy or with         the group —CF₃ or —OCF₃, and the ring of the C₃-C₁₀-cycloalkyl         and the C₁-C₁₀-alkyl optionally can be interrupted by one or         more nitrogen, oxygen and/or sulfur atoms and/or can be         interrupted by one or more ═C═O groups in the ring and/or         optionally one or more possible double bonds can be contained in         the ring, or     -   R² stands for the group

-   -   X stands for oxygen or for the group —NH—, —N(C₁-C₃-alkyl) or         for —OC₃-C₁₀-cycloalkyl, which can be substituted in one or more         places in the same way or differently with a heteroaromatic         compound, or     -   X and R² together form a C₃-C₁₀-cycloalkyl ring, which         optionally can contain one or more heteroatoms and optionally         can be substituted in one or more places with hydroxy,         C₁-C₆-alkyl, C₁-C₆-alkoxy or halogen,     -   A and B, in each case independently of one another, stand for         hydrogen, hydroxy, C₁-C₃-alkyl, C₁-C₆-alkoxy or for the group         —S—CH₃, —SO₂—C₂H₄—OH, —CO—CH₃, —S—CHF₂,         —S—(CH₂)_(n)CH(OH)CH₂N—R³R⁴, —CH₂P(O)OR³OR⁴, —S—CF₃, —SO—CH₃,         —SO₂CF₃, —SO₂—(CH₂)_(n)—N—R³R⁴, —SO₂—NR³R⁴, —SO₂R⁷, —CH—(OH)—CH₃         or for

or

-   -   A and B together can form a group

-   -   R³ and R⁴, in each case independently of one another, stand for         hydrogen, phenyl, benzyloxy, C₁-C₁₂-alkyl, C₁-C₆-alkoxy,         C₂-C₄-alkenyloxy, C₃-C₆-cycloalkyl, hydroxy,         hydroxy-C₁-C₆-alkyl, dihydroxy-C₁-C₆-alkyl, heteroaryl,         heterocyclo-C₃-C₁₀-alkyl, heteroaryl-C₁-C₃-alkyl,         C₃-C₆-cycloalkyl-C₁-C₃-alkyl optionally substituted with cyano,         or for C₁-C₆-alkyl that is optionally substituted in one or more         places in the same way or differently with phenyl, pyridyl,         phenyloxy, C₃-C₆-cycloalkyl, C₁-C₆-alkyl or C₁-C₆-alkoxy,         -   whereby the phenyl itself can be substituted in one or more             places in the same way or differently with halogen,             trifluoromethyl, C₁-C₆-alkyl, C₁-C₆-alkoxy or with the group             —SO₂NR³R⁴,         -   or for the group —(CH₂)_(n)NR³R⁴, —CNHNH₂ or —NR³R⁴ or for

-   -   -   which optionally can be substituted with C₁-C₆-alkyl,

    -   R⁵ stands for hydroxy, phenyl, C₁-C₆-alkyl, C₃-C₆-cycloalkyl,         benzoxy, C₁-C₆-alkylthio or C₁-C₆-alkoxy,

    -   R⁶ stands for the group

-   -   R⁷ stands for halogen, hydroxy, phenyl, C₁-C₆-alkyl, —C₂H₄OH,         —NR³R⁴, or the group

-   -   R⁸, R⁹ and     -   R¹⁰, in each case independently of one another, stand for         hydrogen, hydroxy, C₁-C₆-alkyl, C₃-C₆-cycloalkyl or for the         group

-   -    and     -   n stands for 0-6,         as well as isomers, enantiomers, diastereomers, and salts         thereof, are especially effective.

Those compounds of general formula I in which

-   -   R¹ stands for hydrogen, halogen, C₁-C₃-alkyl, or for the group         —(CH₂)_(n)R⁵,     -   R² stands for —CH(CH₃)—(CH₂)_(n)—R⁵, —CH—(CH₂OH)₂, —(CH₂)_(n)R⁷,         —CH(C₃H₇)—(CH₂)_(n)—R5, —CH(C₂H₅)—(CH₂)_(n)—R⁵, —CH₂—CN,         —CH(CH₃)COCH₃, —CH(CH₃)—C(OH)(CH₃)₂, —CH(CH(OH)CH₃)OCH₃,         —CH(C₂H₅)CO—R⁵, C₂-C₄-alkinyl, —(CH₂)_(n)—COR⁵,         —(CH₂)_(n)—CO—C₁-C₆-alkyl, —(CH₂)_(n)—C(OH)(CH₃)-phenyl,         —CH(CH₃)—C(CH₃)—R⁵, —CH(CH₃)—C(CH₃)(C₂H₅)—R⁵, —CH(OCH₃)—CH₂—R⁵,         —CH₂—CH(OH)—R⁵, —CH(OCH₃)—CHR⁵—CH₃, —CH(CH₃)—CH(OH)—CH₂—CH═CH₂,         —CH(C₂H₅)—CH(OH)—(CH₂)_(n)—CH₃, —CH(CH₃)—CH(OH)—(CH₂)_(n)—CH₃,         —CH(CH₃)—CH(OH)—CH(CH₃)₂, (CH₂OAC)₂, —(CH₂)_(n)—R⁶,         —(CH₂)_(n)—(CF₂)_(n)—CF₃, —CH(CH₂)_(n)—R⁵)₂, —CH(CH₃)—CO—NH₂,         —CH(CH₂OH)-phenyl, —CH(CH₂OH)—CH(OH)—(CH₂)_(n)R⁵,         —CH(CH₂OH)—CH(OH)-phenyl, —CH(CH₂OH)—C₂H₄—R⁵,         —(CH₂)_(n)—C≡C(CH₃)═CH—COR⁵, —CH(Ph)-(CH₂)_(n)—R⁵,         —CH₂)_(n)—COR⁵, —(CH₂)_(n)PO₃(R⁵)₂, —(CH₂)_(n)—COR⁵,         —CH((CH₂)_(n)OR⁵)CO—R⁵, —(CH₂)_(n)CONHCH((CH₂)_(n)R⁵)₂,         —(CH₂)_(n)NH—COR⁵, —CH(CH₂)_(n)R⁵—(CH₂)_(n)C₃-C₁₀-cycloalkyl,         —(CH₂)_(n)—C₃-C₁₀-cycloalky, C₃-C₁₀-cycloalkyl; C₁-C₆-alkyl,         C₃-C₁₀-cycloalkyl, —(CH₂)_(n)—O—(CH₂)_(n)—R⁵, —(CH₂)_(n)—NR³R⁴         that is optionally substituted in one or more places in the same         way or differently with hydroxy, C₁-C₆-alkyl or the group         —COONH(CH₂)_(n)CH₃ or —NR³R⁴,         —CH(C₃H₇)—(CH₂)_(n)—OC(O)—(CH₂)_(n)—CH₃, —(CH₂)_(n)—R⁵,         —C(CH₃)₂—(CH₂)_(n)—R⁵, —C(CH₂)_(n)(CH₃)—(CH₂)_(n)R⁵,         —C(CH₂)_(n)—(CH₂)_(n)R⁵, —CH(t-butyl)-(CH₂)_(n)—R⁵,         —CCH₃(C₃H₇)—(CH₂)_(n)R⁵, —CH(C₃H₇)—(CH₂)_(n)—R⁵, —CH(C₃H₇)—COR⁵,         —CH(C₃H₇)—(CH₂)_(n)—OC(O)—NH-Ph,         —CH((CH₂)_(n)(C₃H₇))—(CH₂)_(n)R⁵,         —CH(C₃H₇)—(CH₂)_(n)—OC(O)—NH-Ph(OR⁵)₃, —NR³R⁴,         —NH—(CH₂)_(n)—NR³R⁴, R⁵—(CH₂)_(n)—C*H—CH(R⁵)—(CH₂)_(n)—R⁵,         —(CH₂)_(n)—CO—NH—(CH₂)_(n)—CO—R⁵, —OC(O)NH—C₁-C₆-alkyl or         —(CH₂)_(n)—CO—NH—(CH₂)_(n)—CH—((CH₂)_(n)R⁵)₂, or for         C₃-C₁₀-cycloalkyl, which is substituted with the group

or for the group

-   -   X stands for oxygen or for the group —NH—, —N(C₁-C₃-alkyl) or

or

-   -   R² stands for the group

or

-   -   X and R² together form a group

-   -   A and B, in each case independently of one another, stand for         hydrogen, hydroxy, C₁-C₃-alkyl, C₁-C₆-alkoxy or for the group         —S—CH₃, —SO₂—C₂H₄—OH, —CO—CH₃, —S—CHF₂,         —S(CH₂)_(n)CH(OH)CH₂N—R³R⁴, —CH₂PO(OC₂H₅)₂, —S—CF₃, —SO—CH₃,         —SO₂CF₃, —SO₂—(CH₂)_(n)—N—R³R⁴, —SO₂—NR³R⁴, —SO₂R⁷, —CH(OH)—CH₃,         —COOH, —CH((CH₂)_(n)R⁵)₂, —(CH₂)_(n)R⁵, —COO—C₁-C₆-alkyl,         —CONR³R⁴ or for

or

-   -   A and B together can form a group

-   -   R³ and R⁴, in each case independently of one another, stand for         hydrogen, phenyl, benzyloxy, C₁-C₁₂-alkyl, C₁-C₆-alkoxy,         C₂-C₄-alkenyloxy, C₃-C₆-cycloalkyl, hydroxy,         hydroxy-C₁-C₆-alkyl, dihydroxy-C₁-C₆-alkyl, heteroaryl,         heterocyclo-C₃-C₁₀-alkyl, heteroaryl-C₁-C₃-alkyl,         C₃-C₆-cycloalkyl-C₁-C₃-alkyl that is optionally substituted with         cyano, or for C₁-C₆-alkyl that is optionally substituted in one         or more places in the same way or differently with phenyl,         pyridyl, phenyloxy, C₃-C₆-cycloalkyl, C₁-C₆-alkyl or         C₁-C₆-alkoxy, whereby the phenyl itself can be substituted in         one or more places in the same way or differently with halogen,         trifluoromethyl, C₁-C₆-alkyl, C₁-C₆-alkoxy or with the group         —SO₂NR³R⁴, or for the group —(CH₂)_(n)NR³R⁴, —CNHNH₂ or —NR³R⁴         or for

-   -    which optionally can be substituted with C₁-C₆-alkyl,     -   R⁵ stands for hydroxy, phenyl, C₁-C₆-alkyl, C₃-C₆-cycloalkyl,         benzoxy, C₁-C₆-alkylthio or C₁-C₆-alkoxy,     -   R⁶ stands for the group

-   -   R⁷ stands for halogen, hydroxy, phenyl, C₁-C₆-alkyl,         —(CH₂)_(n)OH, —NR³R⁴ or the group

-   -   R⁸, R⁹ and     -   R¹⁰ stand for hydrogen, hydroxy, C₁-C₆-alkyl or for the group         —(CH₂)_(n)—COOH, and     -   n stands for 0-6,         as well as isomers, diastereomers, enantiomers and salts         thereof, have proven quite especially effective.

The compounds according to the invention essentially inhibit cyclin-dependent kinases, upon which is based their action, for example, against cancer, such as solid tumors and leukemia; auto-immune diseases such as psoriasis, alopecia, and multiple sclerosis, chemotherapy-induced alopecia and mucositis; cardiovascular diseases such as stenoses, arterioscleroses and restenoses; infectious diseases, such as, e.g., by unicellular parasites, such as trypanosoma, toxoplasma or plasmodium, or produced by fungi; nephrological diseases, such as, e.g., glomerulonephritis, chronic neurodegenerative diseases, such as Huntington's disease, amyotropic lateral sclerosis, Parkinson's disease, AIDS dementia and Alzheimer's disease; acute neurodegenerative diseases, such as ischemias of the brain and neurotraumas; viral infections, such as, e.g., cytomegalic infections, herpes, Hepatitis B and C, and HIV diseases.

The eukaryotic cell division ensures the duplication of the genome and its distribution to the daughter cells by passing through a coordinated and regulated sequence of events. The cell cycle is divided into four successive phases: the G1 phase represents the time before the DNA replication, in which the cell grows and is sensitive to external stimuli. In the S phase, the cell replicates its DNA, and in the G2 phase, preparations are made for entry into mitosis. In mitosis (M phase), the replicated DNA separates, and cell division is completed.

The cyclin-dependent kinases (CDKs), a family of serine/threonine kinases, whose members require the binding of a cyclin (Cyc) as a regulatory subunit in order for them to activate, drive the cell through the cell cycle. Different CDK/Cyc pairs are active in the various phases of the cell cycle. CDK/Cyc pairs that are important to the basic function of the cell cycle are, for example, CDK4(6)/CycD, CDK2/CycE, CDK2/CycA, CDK1/CycA and CDK1/CycB. Some members of the CDK enzyme family have a regulatory function by influencing the activity of the above-mentioned cell cycle CDKs, while no specific function could be associated with other members of the CDK enzyme family. One of the latter, CDK5, is distinguished in that it has an atypical regulatory subunit (p35) that deviates from the cyclins, and its activity is highest in the brain.

The entry into the cell cycle and the passage through the “restriction points,” which marks the independence of a cell from further growth signals for the completion of the cell division that has begun, are controlled by the activity of the CDK4(6)/CycD and CDK2/CycE complexes. The essential substrate of these CDK complexes is the retinoblastoma protein (Rb), the product of the retinoblastoma tumor suppressor gene. Rb is a transcriptional co-repressor protein. In addition to other, still largely little understood mechanisms, Rb binds and inactivates transcription factors of the E2F type and forms transcriptional repressor complexes with histone-deacetylases (HDAC) (Zhang, H. S. et al. (2000). Exit from G1 and S Phase of the Cell Cycle is Regulated by Repressor Complexes Containing HDAC-Rb-hSWI/SNF and Rb-hSWI/SNF. Cell 101, 79-89). By the phosphorylation of Rb by CDKs, bonded E2F transcription factors are released and result in transcriptional activation of genes, whose products are required for the DNA synthesis and the progression through the S-phase. In addition, the Rb-phosphorylation brings about the breakdown of the Rb-HDAC complexes, by which additional genes are activated. The phosphorylation of Rb by CDK's is to be treated as equivalent to exceeding the “restriction points.” For the progression through the S-phase and its completion, the activity of the CDK2/CycE and CDK2/CycA complexes is necessary, e.g., the activity of the transcription factors of the E2F type is turned off by means of phosphorylation by CDK2/CycA as soon as the cells are entered into the S-phase. After replication of DNA is complete, the CDK1 in the complex with CycA or CycB controls the entry into and the passage through phases G2 and M (FIG. 1).

According to the extraordinary importance of the cell-division cycle, the passage through the cycle is strictly regulated and controlled. The enzymes that are necessary for the progression through the cycle must be activated at the correct time and are also turned off again as soon as the corresponding phase is passed. Corresponding control points (“checkpoints”) stop the progression through the cell cycle if DNA damage is detected, or the DNA replication or the creation of the spindle device is not yet completed.

The activity of the CDKs is controlled directly by various mechanisms, such as synthesis and degradation of cyclins, complexing of the CDKs with the corresponding cyclins, phosphorylation and dephosphorylation of regulatory threonine and tyrosine radicals, and the binding of natural inhibitory proteins. While the amount of protein of the CDKs in a proliferating cell is relatively constant, the amount of the individual cyclins oscillates with the passage through the cycle. Thus, for example, the expression of CycD during the early G1 phase is stimulated by growth factors, and the expression of CycE is induced after the “restriction points” are exceeded by the activation of the transcription factors of the E2F type. The cyclins themselves are degraded by the ubiquitin-mediated proteolysis. Activating and inactivating phosphorylations regulate the activities of the CDKs, for example phosphorylate CDK-activating kinases (CAKs) Thr160/161 of the CDK1, while, by contrast, the families of Wee1/Myt1 inactivate kinases CDK1 by phosphorylation of Thr14 and Tyr15. These inactivating phosphorylations can be destroyed in turn by cdc25 phosphatases. The regulation of the activity of the CDK/Cyc complexes by two families of natural CDK inhibitor proteins (CKIs), the protein products of the p21 gene family (p21, p27, p57) and the p16 gene family (p15, p16, p18, p19) is very significant. Members of the p21 family bind to cyclin complexes of CDKs 1,2,4,6, but inhibit only the complexes that contain CDK1 or CDK2. Members of the p16 family are specific inhibitors of the CDK4- and CDK6 complexes.

The plane of control point regulation lies above this complex direct regulation of the activity of the CDKs. Control points allow the cell to track the orderly sequence of the individual phases during the cell cycle. The most important control points lie at the transition from G1 to S and from G2 to M. The G1 control point ensures that the cell does not initiate any DNA synthesis unless it has proper nutrition, interacts correctly with other cells or the substrate, and its DNA is intact. The G2/M control point ensures the complete replication of DNA and the creation of the mitotic spindle before the cell enters into mitosis. The G1 control point is activated by the gene product of the p53 tumor suppressor gene. p53 is activated after detection of changes in metabolism or the genomic integrity of the cell and can trigger either a stopping of the cell cycle progression or apoptosis. In this case, the transcriptional activation of the expression of the CDK inhibitor protein p21 by p53 plays a decisive role. A second branch of the G1 control point comprises the activation of the ATM and Chk1 kinases after DNA damage by UV light or ionizing radiation and finally the phosphorylation and the subsequent proteolytic degradation of the cdc25A phosphatase (Mailand, N. et al. (2000). Rapid Destruction of Human cdc25A in Response to DNA Damage. Science 288, 1425-1429). A shutdown of the cell cycle results from this, since the inhibitory phosphorylation of the CDKs is not removed. After the G2/M control point is activated by damage of the DNA, both mechanisms are involved in a similar way in stopping the progression through the cell cycle.

The loss of the regulation of the cell cycle and the loss of function of the control points are characteristics of tumor cells. The CDK-Rb signal path is affected by mutations in over 90% of human tumor cells. These mutations, which finally result in inactivating phosphorylation of the RB, include the over-expression of D- and E-cyclins by gene amplification or chromosomal translocations, inactivating mutations or deletions of CDK inhibitors of the p16 type, as well as increased (p27) or reduced (CycD) protein degradation. The second group of genes, which are affected by mutations in tumor cells, codes for components of the control points. Thus p53, which is essential for the G1 and G2/M control points, is the most frequently mutated gene in human tumors (about 50%). In tumor cells that express p53 without mutation, it is often inactivated because of a greatly increased protein degradation. In a similar way, the genes of other proteins that are necessary for the function of the control points are affected by mutations, for example ATM (inactivating mutations) or cdc25 phosphatases (over-expression).

Convincing experimental data indicate that CDK2/Cyc complexes occupy a decisive position during the cell cycle progression: (1) Both dominant-negative forms of CDK2, such as the transcriptional repression of the CDK2 expression by anti-sense oligonucleotides, produce a stopping of the cell cycle progression. (2) The inactivation of the CycA gene in mice is lethal. (3) The disruption of the function of the CDK2/CycA complex in cells by means of cell-permeable peptides resulted in tumor cell-selective apoptosis (Chen, Y. N. P. et al. (1999). Selective Killing of Transformed Cells by Cyclin/Cyclin-Dependent Kinase 2 Antagonists. Proc. Natl. Acad. Sci. USA 96, 4325-4329).

Changes of the cell cycle control play a role not only in carcinoses. The cell cycle is activated by a number of viruses, both by transforming viruses as well as by non-transforming viruses, to make possible the replication of viruses in the host cell. The false entry into the cell cycle of normally post-mitotic cells is associated with various neurodegenerative diseases. The mechanisms of the cell cycle regulation, their changes in diseases and a number of approaches to develop inhibitors of the cell cycle progression and especially the CDKs were already described in a detailed summary in several publications (Sielecki, T. M. et al. (2000). Cyclin-Dependent Kinase Inhibitors: Useful Targets in Cell Cycle Regulation. J. Med. Chem. 43, 1-18; Fry, D. W. & Garrett, M. D. (2000). Inhibitors of Cyclin-Dependent Kinases as Therapeutic Agents for the Treatment of Cancer. Curr. Opin. Oncol. Endo. Metab. Invest. Drugs 2, 40-59; Rosiania, G. R. & Chang, Y. T. (2000). Targeting Hyperproliferative Disorders with Cyclin-Dependent Kinase Inhibitors. Exp. Opin. Ther. Patents 10, 215-230; Meijer L. et al. (1999). Properties and Potential Applications of Chemical Inhibitors of Cyclin-Dependent Kinases. Pharmacol. Ther. 82, 279-284; Senderowicz, A. M. & Sausville, E. A. (2000). Preclinical and Clinical Development of Cyclin-Dependent Kinase Modulators. J. Natl. Cancer Inst. 92, 376-387).

To use the compounds according to the invention as pharmaceutical agents, the latter are brought into the form of a pharmaceutical preparation, which in addition to the active ingredient for enteral or parenteral administration contains suitable pharmaceutical, organic or inorganic inert carrier materials, such as, for example, water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, etc. The pharmaceutical preparations can be present in solid form, for example as tablets, coated tablets, suppositories, or capsules, or in liquid form, for example as solutions, suspensions, or emulsions. Moreover, they optionally contain adjuvants, such as preservatives, stabilizers, wetting agents or emulsifiers; salts for changing the osmotic pressure or buffers. These pharmaceutical preparations are also subjects of this invention.

For parenteral administration, especially injection solutions or suspensions, especially aqueous solutions of active compounds in polyhydroxyethoxylated castor oil, are suitable.

As carrier systems, surface-active adjuvants such as salts of bile acids or animal or plant phospholipids, but also mixtures thereof, as well as liposomes or their components can also be used.

For oral administration, especially tablets, coated tablets or capsules with talc and/or hydrocarbon vehicles or binders, such as, for example, lactose, corn or potato starch, are suitable. The administration can also be carried out in liquid form, such as, for example, as a juice, to which optionally a sweetener is added.

Enteral, parenteral and oral administrations are also subjects of this invention.

The dosage of the active ingredients can vary depending on the method of administration, age and weight of the patient, type and severity of the disease to be treated and similar factors. The daily dose is 0.5-1000 mg, preferably 50-200 mg, whereby the dose can be given as a single dose to be administered once or divided into two or more daily doses.

Subjects of this invention also include the use of compounds of general formula I for the production of a pharmaceutical agent for treating cancer, auto-immune diseases, cardiovascular diseases, chemotherapy agent-induced alopecia and mucositis, infectious diseases, nephrological diseases, chronic and acute neurodegenerative diseases and viral infections, whereby cancer is defined as solid tumors and leukemia; auto-immune diseases are defined as psoriasis, alopecia and multiple sclerosis; cardiovascular diseases are defined as stenoses, arterioscleroses and restenoses; infectious diseases are defined as diseases that are caused by unicellular parasites; nephrological diseases are defined as glomerulonephritis; chronic neurodegenerative diseases are defined as Huntington's disease, amyotrophic lateral sclerosis, Parkinson's disease, AIDS dementia and Alzheimer's disease; acute neurodegenerative diseases are defined as ischemias of the brain and neurotraumas; and viral infections are defined as cytomegalic infections, herpes, hepatitis B or C, and HIV diseases.

Subjects of this invention also include pharmaceutical agents for treating the above-cited diseases, which contain at least one compound according to general formula I, as well as pharmaceutical agents with suitable formulation substances and vehicles.

The compounds of general formula I according to the invention are, i.a., excellent inhibitors of the cyclin-dependent kinases, such as CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8 and CDK9, as well as the glycogen-synthase-kinase (GSK-3β).

If the production of the starting compounds is not described, these compounds are known or can be produced analogously to known compounds or to processes that are described here. It is also possible to perform all reactions that are described here in parallel reactors or by means of combinatory operating procedures.

The isomer mixtures can be separated into the enantiomers or E/Z isomers according to commonly used methods, such as, for example, crystallization, chromatography or salt formation.

The production of the salts is carried out in the usual way by a solution of the compound of formula I being mixed with the equivalent amount of or excess base or acid, which optionally is in solution, and the precipitate being separated or the solution being worked up in the usual way.

Production of the Compounds According to the Invention

The following examples explain the production of the compounds according to the invention, without the scope of the claimed compounds being limited to these examples.

The compounds of general formula I according to the invention can be produced according to the following general diagrams of the process:

[Key:] gleiche Methode=Same Method EXAMPLE 1 Production of 5-Bromo-N2-(4-difluoromethylthiophenyl)-N4-2-propynyl-2,4-pyrimidine diamine (Carried Out According to Process Diagram 1) (Compound 23)

245 mg (1 mmol) of 2-chloro-4-2-propynylaminopyrimidine is dissolved in 2 ml of acetonitrile, and a suspension of 4-(difluoromethylthio)-aniline hydrochloride [produced from 352 mg (2 mmol) of 4-(difluoromethylthio)-aniline, 1 ml of acetonitrile and 0.5 ml of aqueous HCl (4M in dioxane)] is added at room temperature. Then, the reaction mixture is refluxed overnight under N₂ atmosphere. After cooling, the mixture is filtered, the remaining solid phase is washed with H₂O and dried. A yield of 328 mg (85%) of the product can be expected

6H 8.25(s, 1H) Yield: 2C 7.86(d, 2H) 85% H 7.51(d, 2H) 7.38 (t, 56.8 Hz, 1H) Melting point: >235° C. 4C 4.18(m, 2H) H⁻ 3.16(sb, 1H) 10.24(sb, 1H) NH 8.17(sb, 1H)

EXAMPLE 2 Production of 5-bromo-N-(3-(oxiranylmethoxy)phenyl)-2-(2-propynyloxy)-2-pyrimidinamine (compound 51) and Carried Out According to Process Diagram 2

1.55 g (4.9 mmol) of compound 20 is dissolved in 5.5 ml of epibromohydrin, and 1.38 g of K₂CO₃ and 65 mg of tetrabutylammonium bromide are added to it. The reaction mixture is stirred under nitrogen atmosphere at 100° C. for 1 hour. After ethyl acetate is added, the resulting precipitate is collected and recrystallized from ethanol. The product yield is 1.15 g (62%) as a white powder.

6H 8.45(s, 1H) 2CH 7.47(s, 1H) 7.32(d, 1H) Yield: 62% 7.20(t, 1H) 6.40(d, 1H) Melting point: 173° C. 4.32(dd, 1H) 3.82(dd, 1H) 3.3-3.4(m, 1H) 2.87(t, 1H) 2.72(dd, 1H) 4CH 5.13(d, 2H) 3.67(t, 1H) NH 9.84(sb, 1H)

Substance 40 is produced analogously to Example 2.

6-H 8.36(s, 1H) Chromatography: 2CH 7.60(d, 1H) H/EA 1:3 0.5% TEA 6.91(d, 1H) 4.28(dd, 1H) 3.79(dd, 1H) Yield: 38% 3.31(m, 1H) 2.84(dd, 1H) Melting point: 140-141° C. 2.70(dd, 1H) 4CH 5.07(d, 12H) 3.65(t, 1H) NH 9.65(sb, 1H) OH

EXAMPLE 3 Production of 1-(4-((5-bromo-4-(2-propynyloxy)-pyrimidin-2-yl)-amino)phenoxy)-3-(4-phenylpiperazin-1-yl)-2-propanol (Compound 41)

0.2 ml of a 0.5 M 4-phenylpiperazine solution in DMPU is added to a solution of 19 mg (0.05 mmol) of substance 51 in N,N′-dimethylpropylurea (DMPU). The reaction mixture is kept for 18 hours at a temperature of 80° C. After cooling, 3.5 ml of tertiary butyl methyl ether is added, and the organic phase is extracted 5 times with 1.5 ml of H₂O and then evaporated in a vacuum. The remaining residue is chromatographed on 1.7 g (15 μM) of Lichrosphere Si60 (gradient: dichloromethane/hexane 1:1 to DCM and then dichloromethane/methanol 99:1 to 93:7). A product yield of 17 mg (64%) is achieved.

Similarly produced are also the following compounds:

No. Structure 96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

The following compounds were similarly produced in the described examples.

No. Structure Name 28

5-Bromo-N2-(4-(2-diethylaminoethylsulfonyl)phenyl)-N4-2-propynyl-2,4-pyrimidine diamine 30

1-(4-[5-Bromo-4-(2-propynylamino)-2-pyrimidinyl]amino-phenylthio)-3-(diethylamino)-2-propanol 32

5-Bromo-N2-(3-phenylsulfonylphenyl)-N4-2-propynyl-2,4-pyrimidine diamine 33

N-[4-[[5-Bromo-4-(2-propynylamino)-2-pyrimidinyl]amino]-benzenesulfonyl]morpholine 41

1-(4-((5-Bromo-4-(2-propynyloxy)-pyrimidin-2-yl)-amino)phenoxy)-3-(4-phenylpiperazin-1-yl)-2-propanol 57

N-[5-Bromo-4-((2R)-1-hydroxy-4-methyl-2-butylamino)-2-pyrimidinyl]-indazol-5-amine 58

4-[[5-Fluoro-4-((2R)-1-hydroxy-3-methyl-2-butylamino)-2-pyrimidinyl]amino]-benzenesulfonamide 59

4-[[5-Iodo-4-((2R)-1-hydroxy-3-methyl-2-butylamino)-2-pyrimidinyl]amino]-benzenesulfonamide 62

4-[[5-Fluoro-4-(2-propynylamino)-2-pyrimidinyl]amino]-benzenesulfonamide 65

4-[[5-Ethyl-4-(2-propynylamino)-2-pyrimidinyl]amino]-benzenesulfonamide 66

1-[4-[(5-Iodo-4-((2R)-1-hydroxy-3-methyl-2-butylamino)-2-pyrimidinyl)amino]phenyl]-ethanone 68

1-[4-[(5-Ethyl-4-((2R)-1-hydroxy-3-methyl-2-butylamino)-2-pyrimidinyl)amino]phenyl]-ethanone 72

4-[[5-Bromo-4-(2-(2-oxo-imidazolin-1-yl)ethylamine)-2-pyrimidinyl]amino]-benzenesulfonamide 73

4-[[5-Bromo-4-(2,2,3,3,3-pentafluoropropyloxy)-2-pyrimidinyl]amino]-benzenesulfonamide 75

4-[[5-Bromo-4-(1,3-bisacetoxy-2-propyloxy)-2-pyrimidinyl]amino]-benzenesulfonamide 76

4-[[5-Bromo-4-(1,3-dihydroxy-2-propyloxy)-2-pyrimidinyl]amino]-benzenesulfonamide 79

N□-(5-Bromo-2-(4-sulfamoylphenyl)amino-pyrimidin-4-yl)-L-alanine amide 83

1-[4-[(5-Bromo-4-(2-propynylamino)-2-pyrimidinyl)amino]phenyl]-ethanol

The following compounds were produced analogously to the described synthesis processes according to Diagram 1 or 2:

All NMR spectra are measured in the indicated solvent or in DMSO.

[Key to the Following Tables and Diagrams:]

-   Bsp.-Nr. [Beispiel Nr.]=Example No. -   Chromatographie Ausbeute=Chromatography yield -   Schmp.=Melting point -   Kristallisiert=Crystallized -   Masse=Mass -   krist. Wasser=Crystallized water -   Verbindung=Compound -   Hitze=Heat

Bsp.-Nr. 37 38 39 5 6-H 8.34(s, 1H) 8.39(s, 1H) 8.30(s, 1H) 8.00(s, 1H) 2CH 12.88 9.28(s, 1H) 7.74(s, 1H) 7.52(d, 2H) (sb, 1H) 8.79(s, 1H) 7.44(d, 1H) 6.65(d, 2H) 8.07(s, 1H) 7.70(d, 1H) 7.22(d, 1H) 7.93(s, 1H) 8.04(d, 1H) 3.98(t, 2H) 7.41(d, 1H) 3.13(t, 2H) 7.56 2.99(s, 3H) 4CH (dd, 1H) 4.19(d, 2H) 4.16(d, 2H) 4.09(d, 2H) 3.22(sb, 1H) 3.28(sb, 1H) 3.09(s, 1H) NH 4.15 10.43(sb, 1H) 10.6(1H) 9.00(s, 1H) (dd, 2H) 8.45(sb, 1H) 8.75(1H) 8.96(s, 1H) 3.18(t, 1H) 7.31(t, 1H) 9.30 (sb, 1H) 7.39 (tb, 1H) Chro- EA + 0.5% — Kristallisiert — mato- TEA MeOH graphie 10% 36% 73% 20% Aus- beute Schmp. 231° C. >235° C. 237° C. 157° C.

Beispiel 16 24 26 35 Nr. 6-H 8.80(s, 1H) 8.30(s, 1H) 8.18(s, 1H) 8.14(s, 1H) 2CH 7.67(d, 2H) 7.94(d, 2H) 7.67(s, 1H) 8.28(s, 1H) 7.27(d, 2H) 7.63(d, 2H) 7.54(d, 1H) 7.98(d, 1H) 2.47(s, 3H) 7.24(t, 1H) 7.41(t, 1H) 6.92(d, 1H) 7.25(d, 1H) 4CH 4.17(dd, 2H) 4.17(dd, 2H) 4.20(dd, 2H) 4.14(dd, 2H) 3.75(t, 1H) 3.18(t, 1H) 3.12(sb, 1H) 3.04(sb, 1H) NH 10.55 10.45 9.78(sb, 1H) 9.58(sb, 1H) (sb, 1H) (sb, 1H) 7.95(sb, 1H) 7.46(sb, 1H) 8.68(sb, 1H) 8.22(sb, 1H) Chrom. — — — — Aus- 94% 86% 73% 69% beute Schmp. 232-234° C. 160° C. 194° C. 143° C.

Beispiel 27 36 34 21 Nr. 6-H 8.18(s, 1H) 8.26(s, 1H) 8.25(s, 1H) 8.17(s, 1H) 2CH 8.73(s, 1H) 8.12(s, 1H) 8.16.(s, 1H) 8.74(s, 1H) 7.62(d, 1H) 7.35-7.55 7.43(d, 1H) 7.43(d, 1H) 7.72(t, 1H) (m, 3H) 7.52(t, 1H) 7.52(t, 1H) 8.31(d, 1H) 8.06(d, 1H) 8.01(d, 1H) 8.08(d, 1H) 2.78(m, 2H) 3.43(t, 2H) 1.35(mc, 2H) 3.70(t, 2H) 1.24(mc, 2H) 0.80(t, 3H) 4CH 4.18(dd, 2H) 4.21(d, 2H) 4.20(dd, 2H) 3.06(t, 1H) 4.21(d, 2H) 3.09(sb, 1H) 3.08(t, 1H) NH 10.02(s, 1H) 3.09(sb, 1H) 10.3(sb, 1H) 9.79(s, 1H) 7.49(sb, 1H) 9.68(sb, 1H) 8.13(sb, 1H) 7.55(tb, 1H) OH 7.30(sb, 2H) 4.90(sb, 1H) Chrom. — krist. EtOH — — Aus- 69% 64% 87% 59% beute Schmp. 144° C. 219° C. 220° C. 192.5-193.5° C.

Beispiel 31 25 23 11 Nr. 6-H 8.25(s, 1H) 8.14(s, 1H) 8.25(s, 1H) 8.29(s, 1H) 2CH 7.65(d, 2H) 8.01(d, 2H) 7.86(d, 2H) 7.95(d, 2H) 7.24(d, 2H) 7.56(d, 2H) 7.51(d, 2H) 7.78(d, 2H) 3.19 2.70(s, 3H) 7.38 (d, 21.3 Hz, 2H) (t, 56.8 Hz, 1H) 3.95 4CH (mc, 4H) 4.15(dd, 2H) 4.18(m, 2H) 4.19(d, 2H) 1.20(t, 6H) 3.14(t, 1H) 3.16(sb, 1H) 3.18(sb, 1H) NH 9.69(sb, 1H) 10.24(sb, 1H) 10.40 4.17(sb, 2H) 7.55(tb, 1H) 8.17(sb, 1H) (sb, 1H) 3.15(sb, 1H) 8.24(sb, 1H) 10.19 7.15(sb, 2H) (sb, 1H) 8.34(sb, 1H) Chrom. EA krist. DCM/MeOH — krist. Aus- H/DIPE 95:5 85% DIPE/EtOH beute 23% 25% 17% Schmp. 198° C. 217-218° C. >235° C. >235° C.

Beispiel 44 45 4 Nr. 6-H 8.34(s, 1H) 8.34(s, 1H) 8.23 n(sb, 1H) 2CH 7.93(d, 2H) 7.74(mc, 4H) 7.39(d, 2H) 7.79(d, 2H) 6.79(d, 2H) 4CH 4.20(sb, 2H) 4.55(q, 1H) 3.52-3.71(2H) 3.31(sb, 1H) 1.98(dq, 2H) 3.97(mc, 1H) 0.94(t, 3H) 1.96(mc, 1H) 3.61(s, 3H) 0.91(d, 3H) NH 11.03(sb, 1H) 10.60(s, 1H) 0.85(d, 3H) 9.04(sb, 1H) 7.97(d, 1H) 10.35(sb, 1H) 7.34(sb, 2H) 7.31(db, 2H) 7.76(sb, 1H) Chrom. krist. EtOH krist. EtOH — Aus- 27% 48% 52% beute Schmp. 252° C. 235° C. 242-243° C.

Beispiel 10 15 3 19 Nr. 6-H 8.27(s, 1H) 8.17(s, 1H) 7.97.(s, 1H) 8.20-8.35 2H 7.80 7.60(d, 2H) 7.44(d, 2H) (2H) (mc, 4H) 7.24(d, 2H) 6.67(d, 2H) 7.90(sb, 1H) 2.44(s, 3H) 7.50-7.64 (2H) 3.46(t, 2H) 4H 3.5-3.7(2H) 3.50-3.65 3.70(t, 2H) 3.66 40.1(mc, 1H) (4H) (mc, 2H) 1.98(mc, 1H) 4.12(mc, 1H) 3-56-3.66 n. obs. 0.94(d, 3H) (4H) 2.04 0.90(d, 3H) 4.28(mc, 1H) NH (mc, 1H) 9.95(sb, 1H) OH 0.97(d, 3H) 6.96(sb, 1H) 8.98(sb, 1H) 0.94(d, 3H) ca.4, sehr 5.97(db, 1H) 10.40 breit 8.90(sb, 1H) NH and OH (sb, 1H) 4.80(tb, 2H) sind sehr 7.18(sb, 2H) breit n. obs. Chrom. — — — Kristallisiert Wasser Aus- 43% 27% 76% 52% beute Schmp. 252-253° C. 192-193° C. 257-258° C. 209-210° C.

Beispiel 9 14 55 50 Nr. 6-H 8.30(s, 1H) 8.30(s, 1H) 8.11(s, 1H) 8.17(s, 1H) 2H 7.82 7.55(d, 2H) 7.87(s, 4H) 7.95(d, 2H) (mc, 4H) 7.30(d, 2H) 2.50(s) 7.86(d, 2H) 2.48(s, 3H) 2.50(s) 4H 3.54-3.68 4.19(mc, 1H) 4.17(dd, 2H) 3.63 (4H) 3.61(mc, 4H) 3.13(t, 1H) (mc, 4H) 4.24(mc, 1H) NH 4.24 9.73(s, 1H) 9.81(s, 1H) OH (mc, 1H) 10.63(sb, 1H) 6.20(s, 1H) 7.58(t, 1H) 7.60(sb, 1H) 4.88(t, 2H) 10.59(b, 1H) 4.4(b) 7.2(sb) 6.1(sb) Chrom. Kristallisiert Kristallisiert — Aus- MeOH MeOH/DIPE beute 24% 91% 27% 56% Schmp. 247-248° C. 233-234° C. 228-229° C. 241° C.

Beispiel 46 13 52 53 Nr. 6-H 8.07s, 1H) 8.00(s, 1H) 8.09(s, 1H) 8.11(s, 1H) 2H 7.91(d, 2H) 7.68(d, 2H) 7.88(s, 4H) 7.86(s, 4H) 7.69(d, 2H) 7.18(d, 2H) not obs. 2.44(s, 3H) 4H 3.30(t, 2H) 3.54(q, 2h9 3.32(t, 2H) 3.62(mc, 2H) n. obs.(mc, 1H) 2.53(t, 2H) 1.20(mc, 1H) 4.06(mc, 1H) 2.40-2.45 0.44(mc, 2H) 2.02(mc, 1H) 0.45 (4H) 0.30(mc, 2H) 0.97(d, 3H) (mc, 2H) 3.58(t, 4H) 0.92(d, 3H) NH 0.30 9.70(s, 1H) 9.70(s, 1H) OH (mc, 2H) 9.20(sb, 1H) 7.21(t, 1H) 6.24(d, 1H) 6.81(tb, 1H) 4.80(sb, 1H) 9.94(s, 1H) 7.21(t, 1H) 7.18(s, 2H) Chrom. H/EA 1:2 — — H/EA 1:2 Aus- 20% 28% 53% 9% beute Schmp. 256° C. 185-186° C. 183° C. 170° C.

Beispiel 1 54 12 60 Nr. 6-H 7.96(s, 1H) 8.22(s, 1H) 8.03(s, 1H) 8.10(s, 1H) 2H 7.43(d, 2H) 7.93(d, 2H) 7.68(d, 2H) 7.92(d, 2H) 6.67(d, 2H) 7.85(d, 2H) 7.19(d, 2H) 7.66(d, 2H) 2.43(s, 3H) not. obs. 2.74(t, 2H) 4H 1.20(d, 3H) 4.26(d, 2H) 1.20(d, 3H) 3.61(mc, 2H) 4.38 3.12(sb, 1H) 4.42(mc, 1H) 4.04(mc, 1H) (mc, 1H) 3.37(dd, 1H) 2.01(mc, 1H) 3.37(dd, 1H) 3.50(dd, 1H) 0.94(d, 3H) 3.48(dd, 1H) 3.34(s, 3H) 0.91(d, 3H) NH 3.28(s, 3H) 9.78(s, 1H) 9.26(s, 1H) 9.72(s, 1H) 8.92(sb, 1H) 7.65(s, 1H) 8.81(sb, 1H) 6.27(d, 1H) OH 7.21(t, 1H) 6.42(d, 1H) 4.80(sb, 1H) 6.20(tb, 1H) 4.70(sb, 1H) Chrom. Kristallisiert Kristallisiert Kristallisiert. Aus- EA DIPE/MeOH EA beute 64% 52% 36% Schmp. 165.5-166° C. 210° C. 91° C. 150-151° C.

Beispiel 7 17 2 18 Nr. 6-H 8.32(s, 1H) 8.08(s, 1H) 7.95(s, 1H) 8.32(s, 1H) 4CH 1.22(d, 3H) 1.21(d, 3H) 3.50(q, 2H) 3.10(m, 2H) 4.46 4.53(mc, 1H) 2.50(t, 2H) 3.52(m, 4H) (mc, 1H) 3.41(dd, 1H) 2.40(t, 4H) 3.77-3.97 3.40(dd, 1H) 3.51(dd, 1H) 3.59(t, 4H) (6H) 3.57(dd, 1H) 3.27(s, 3H) 2CH 3.28(s, 3H) 8.53(s, 1H) 7.45(d, 2H) 7.80(s, 4H) 7.40(d, 1H) 6.66(d, 2H) 8.40(s, 1H) 7.50(t, 1H) 7.55-7.70 7.86(d, 1H) (2H) 3.40(t, 2H) 7.85(d, 1H) 3.68(t, 2H) 3.48(m, 2H) NH 9.65(sb, 1H) 8.94(sb, 1H) 3.70(m, 2H) 10.79 6.47(db, 1H) 8.79(sb, 1H) OH (sb, 1H) 4.84(tb, 1H) 6.70(tb, 1H) 11.16(sb, 1H) 7.84(db, 1H) 10.60(sb, 1H) 7.31(sb, 1H) 8.20(sb, 1H) Chrom. — — kristall. Aus- 25% 10% 62% MeOH beute 50% Schmp. 247° C. Zers. 201-202° C. 227.5-228.5° C. 245° C. Zers.

Beispiel 8(D₂O) Nr. 6-H 8.14(s, 1H) 4CH 3.06(sb, 1H) 3.39(t, 4H) 3.71(sb, 2H) 3.85(sb, 2H) 3.94(t, 2H) 2CH 8.00(d, 2H) 7.72(d, 2H NH OH Chrom. krist. Wasser Aus- 25% beute Schmp. >275° C.

Beispiel 47 6 22 84 Nr. 5-H 8.74(s, 1H) 8.31(s, 1H) 8.31(s, 1H) 8.47(s, 1H) 2CH 7.87(d, 2H) 7.47(d, 2H) 7.76(d, 2H) 4.48(t, 2H) 7.74(d, 2H) 6.71(d, 2H) 7.72(d, 2H) 2.01(mc, 2H) 2.58(s, 3H) 2.44(mc, 2H) 4CH 4.50(t, 2H) 5.04(d, 2H) 5.05(d, 2H) 2.03(mc, 2H) 3.59(t, 1H) 2.57(t, 1H) 7.91(d, 2H) 2.44(mc, 2H) 2NH 10.14(s, 1H) 9.02(sb, 1H) 7.47(sb, 1H) 7.85(d, 2H) 7.21(s, 2H) 9.40(sb, 1H) 2.50(s) 10.19(s, 1H) Chrom. MeOH/DCM — — Aus- 1:9 66% 8% 11% beute 4% Schmp. 186-187° C. 146° C. 165-166° C. 152° C.

Beispiel 86 77 Nr. 5-H 8.47(s, 1H) 8.48(s, 1H) 2CH 4.07(mc, 2H) 5.52(m, 1H) 3.81(mc, 2H) 3.68(d, 4H) 3.60(mc, 2H) 3.48(mc, 4H) 4CH 3.48(mc, 2H) 1.09(t, 6H) 3.41(t, 2H) 7.84(d, 2H) 1.07(t, 3H) 2NH 7.84(d, 2H) 7.74(d, 2H) 7.91(d, 2H) 8.05(vb) 10.18(s, 1H) 3.40(vb) Chrom. — — Aus- 2% 74% beute Schmp. 85° C. 132° C.

Beispiel 40 20 Nr. 6-H 8.36(s, 1H) 8.40(s, 1H) 2CH 7.60(d, 1H) 7.23(s, 1H) 6.91(d, 1H) 6.42(d, 1H) 4.28(dd, 1H) 7.06(t, 1H) 3.79(dd, 1H) 7.18(d, 1H) 3.31(m, 1H) 2.84(dd, 1H) 2.70(dd, 1H) 4CH 5.07(d, 12H) 5.12(d, 2H) 3.65(t, 1H) 3.60(sb, 1H) NH 9.65(sb, 1H) 9.60(sb, 1H) OH 9.21(sb, 1H) Chrom. H/EA 1:3 krist. DIPE Aus- 0.5% TEA 35% beute 38% Schmp. 140-141° C. 174° C.

Beispiel 49 48 29 42 Nr. 6-H 8.14(s, 1H) 8.10(s, 1H) 8.09(s, 1H) 7.87(d, 3.4, 1H) 2H 7.88(d, 2H) 7.92(d, 2H) 8.50(s, 1H) 7.51(d, 2H) 7.69(d, 2H) 7.66(d, 2H) 7.86(d, 1H) 6.66(d, 2H) not. obs. 7.50(t, 1H) 2.74(t, 2H) 7.40(d, 1H) 4H 3.41(q, 2H) 3.61(mc, 2H) 3.40(t, 2H) 4.13(dd, 2H) 2.20(t, 2H) 4.04(mc, 1H) 3.52-3.73 3.08(t, 1H) 1.81(q, 2H) 2.01(mc, 1H) (4H) 0.94(d, 3H) 4.09(mc, 1H) 0.91(d, 3H) 1.98(mc, 1H) 0.97(d, 3H) NH 9.64(s, 1H) 9.72(s, 1H) 0.89(d, 3H) 8.76(s, 1H) 7.64(t, 1H) 7.65(s, 1H) 9.68(s, 1H) 7.74(tb, 1H) OH 3.5(vb 6.27(d, 1H) 6.17(d, 1H) 8.88(s, 1H) 4.80(sb, 1H) 4.74(t, 1H) 4.70(sb, 1H) 4.93(t, 1H) Chrom. — krist. MeOH/DI DCM/EA 2:1 H/EA 1:2 Aus- 9% PE 26% 29% beute 16% Schmp. 262° C. 150-151° C. 163° C.

Beispiel 43 55 89 88 Nr. 6-H 7.93(s, 1H) 8.11(s, 1H) 8.36(s, 1H) 8.29(s, 1H) 2H 7.52(d, 2H) 7.87(s, 4H) 7.7-7.8(5H) 7.73(d, 2H) 6.68(d, 2H) 2.50(s) 7.57(d, 2H) 4H 3.09(s, 1H) 4.19(mc, 1H) 3.66(mc, 2H) 3.7-3.9(2H) 4.14(d, 2H) 3.61(mc, 4H) 4.04(m, 1H) 5.19(m, 1H) 1.99(mc, 1H) 7.2-7.4(5H) 0.94(d, 3H) 0.89(d, 3H) NH 8.98(sb, 2H) 9.73(s, 1H) 11.11(sb, 1H) 10.50(s, 1H) 7.50(s, 1H) 6.20(s, 1H) 5.029(vb) OH 4.88(t, 2H) 7.34(sb, 2H) n. obs. Chrom. H/EA 1:2 krist. MeOH/ — — Aus- 35% DIPE 74% 27% beute 27% Schmp. 168° C. 228° C. 248° C. Zers. 159° C. Zers.

Beispiel 87 92 91 96 Nr. 6-H 8.09(s, 1H) 8.10(s, 1H) 8.09(s, 1H) 8.06(s, 1H) 2H 7.90(d, 2H) 7.91(d, 2H) 7.98(d, 2H) 7.88(d, 2H) 7.82(d, 2H) 7.63(d, 2H) 7.61(d, 2H) 7.69(d, 2H) not. obs 2.39(d, 3H) 2.54(s, 6H) 4H 3.69(td, 2H) 1.21(d, 3H) 1.20(d, 3H) 3.41(m, 2H) 2.84(t, 2H) 4.45(mc, 1H) 4.46(mc, 1H) 1.62(m, 4H) 7.60(s, 1H) 3.38(dd, 1H) 3.47(dd, 1H) 2.41(m, 2H) 6.86(s, 1H) 3.51(dd, 1H) 3.51(dd, 1H) 5.07(s, 2H) 3.38(s, 3H) NH 7.34(tb, 1H) 9.73(sb, 1H) 9.81(sb, 1H) 7.32(s, 5H) 9.72(s, 1H) 7.20(q, 1H) 6.58(db, 1H) 9.64(s, 1H) 7.16(sb, 2H) OH 11.91(sb, 1H) 6.57(d, 1H) Chrom. — H bis H/EA 1:1 H bis H/EA — Aus- 16% 21% 1:1 33% beute 7% Schmp. 210° C. 167-168° C. 105° C. 202° C

Beispiel 97 98 90 85 Nr. 6-H 8.07(s, 1H) 8.10(s, 1H) 8.30(s, 1H) 2H 7.87(s, 4H) 7.86(mc, 4H) 7.95(d, 2H) 2.50(s, 3H) n. obs. 7.69(d, 2H) 2.48(s, 3H) 4H 3.41(m, 2H) 3.68(t, 2H) 3.50(q, 2H) 1.61(m, 4H) 2.68(t, 2H) 1.87(m, 2H) 2.41(m, 2H) 4.08(q, 2H) 2.38(t, 2H) 5.07(s, 2H) 1.17(t, §H) 4.03(q, 2H) 1.13(t, 3H) NH 7.32(s, 5H) 9.74(s, 1H) 10.86(s, 1H) 9.70(s, 1H) 7.18(t, 1H) 8.28(sb, 2H) 7.19(t, 1H) Chrom. — — — Aus- 23% 32% 53% beute Schmp. 152° C. 172 184° C.

Beispiel 63 94 93 80 Nr. 9.73(s, 1H) 10.91(s, 1H) 10.80(s, 1H) 10.88(s, 1H) 8.25(s, 1H) 8.34(s, 1H) 8.30(s, 1H) 8.40(s, 1H) 7.95(d, 2H) 7.80(s, 4H) 7.81(d, 2H) 8.29(m, 1H) 7.67(d, 2H) 7.30(s, 2H) 7.65(d, 2H) 7.79(s, 4H) 7.21(s, 3H) 4.35(m, 1H) 7.30(m, 8H) 7.31(s, 2H) 4.12(s, 2H) 3.58(m, 2H) 4.95(d, 1H) 4.75(dd, 1H) 3.12(s, 1H) 2.47(m, 2H) 4.38(m, 1H) 3.65(m, 1H) 2.03(s, 3H) 3.59(d, 1H) 3.49(m, 1H) 1.91(m, 2H) 2.10(m, 2H) Aus- 61% 24% 70% 51% beute Schmp. 220 168 243 Masse 428(EI) 462(ES) 494(ES) 427(EI)

Beispiel 120 121 122 123 Nr. 9.65(s, 1H) 9.68(s, 1H) 11.30(s, 1H) 10.79(s, 1H) 8.12(s, 1H) 8.11(s, 1H) 8.11(d, 1H) 8.35(s, 1H) 7.89(d, 2H) 7.93(t, 1H) 7.85(d, 2H) 8.25(s, 1H) 7.65(d, 2H) 7.90(d, 2H) 7.72(d, 2H) 7.80(s, 4H) 7.15(s, 2H) 7.65(d, 2H) 7.31(s, 2H) 7.30(s, 2H) 6.06(d, 1H) 7.15(s, 2H) 6.71(d, 1H) 3.41(m, 2H) 4.71(t, 1H) 7.07(t, 1H) 3.85(m, 8H) 2.22(t, 2H) 4.18(m, 1H) 3.65(m, 2H) 1.60(m, 4H) 3.67(t, 1H) 3.56(s, 3H) 1.30(m, 2H) 0.95(s, 9H) 3.07(q, 2H) 2.45(t, 2H) 2.30(t, 2H) 1.65(p, 2H) Aus- 49% 24% 80% 73% beute Schmp. 252 Masse 445(EI) 516(EI) 334(EI) 459(EI)

Beispiel Nr. 95 124 125 126 11.19(s, 1H) 9.62(s, 1H) 9.62(s, 1H) 10.91(s, 1H) 8.37(s, 1H) 8.04(s, 1H) 8.04(s, 1H) 8.38(s, 1H) 8.11(d, 1H) 7.88(m, 3H) 7.86(d, 2H) 7.83(d, 2H) 7.80(s, 4H) 7.66(d, 2H) 7.66(d, 2H) 7.77(d, 2H) 7.31(s, 2H) 7.13(s, 3H) 7.12(s, 3H) 7.28(s, 2H) 3.91(m, 1H) 3.58(s, 3H) 3.58(s, 3H) 7.04(d, 1H) 1.89(m, 4H) 3.40(m, 2H) 3.40(m, 2H) 6.40(br, 3H) 1.67(m, 1H) 3.05(m, 2H) 2.30(t, 2H) 4.35(m, 1H) 1.55(m, 2H) 2.25(m, 2H) 1.60(m, 4H) 3.87(m, 1H) 1.34(m, 2H) 2.05(m, 2H) 1.32(m, 2H) 3.60(d, 2H) 1.15(m, 1H) 1.60(m, 5H) 3.41(dd, 1H) 1.32(m, 3H) 3.28(dd, 1H) Aus- 29% 25% 27% 46% beute Schmp. 255 218 Masse 425(EI) 557(ES) 471(EI) 449(EI)

Beispiel 127 128 129 130 Nr. 9.96(s, 1H) 9.60(s, 1H) 9.67(s, 1H) 9.65(s, 1H) 8.12(s, 1H) 8.05(s, 1H) 8.07(s, 1H) 8.08(s, 1H) 7.85(d, 2H) 7.90(d, 2H) 7.87(d, 2H) 7.87(d, 2H) 7.69(d, 2H) 7.69(d, 2H) 7.75(d, 2H) 7.64(d, 2H) 7.20(s, 2H) 7.42(d, 1H) 7.13(s, 2H) 7.14(s, 2H) 6.78(d, 1H) 7.16(m, 3H) 6.40(d, 1H) 6.53(d, 1H) 4.35(m, 1H) 4.57(t, 2H) 4.91(br, 1H) 4.62(d, 1H) 3.48(m, 2H) 3.70(m, 1H) 4.23(m, 1H) 3.90(br, 1H) 1.65(m, 7H) 3.4(m, 5H) 3.52(m, 2H) 3.40(br, 1H) 1.10(m, 6H) 2.10(t, 2H) 1.21(d, 3H) 1.88(m, 4H) 1.55(m, 4H) 1.50(m, 2H) 1.30(m, 2H) 1.30(m, 2H) Aus- 18% 94% 61% 58% beute Schmp. 220 259 262 Masse 485(EI) 531(ES) 403(EI) 443(EI)

Beispiel 131 132 133 134 Nr. 9.62(s, 1H) 9.70(s, 1H) 9.69(s, 1H) 10.85(s, 1H) 8.08(s, 1H) 8.11(s, 1H) 8.11(s, 1H) 8.31(s, 1H) 7.92(d, 2H) 7.90(d, 2H) 7.88(d, 2H) 7.90(d, 1H) 7.67(d, 2H) 7.60(d, 2H) 7.66(d, 2H) 7.85(d, 2H) 7.23(s, 2H) 7.21(q, 1H) 7.15(s, 2H) 7.75(d, 2H) 6.75(t, 1H) 5.25(d, 1H) 6.52(d, 1H) 7.54(s, 1H) 3.22(d, 2H) 4.77(t, 1H) 4.35(dd, 1H) 3.90(m, 1H) 1.95(s, 3H) 4.02(m, 1H) 2.29(m, 1H) 3.38(t, 2H) 1.60(m, 12H) 3.60(m, 2H) 1.07(d, 3H) 2.78(br, 2H) 2.39(d, 3H) 0.91(d, 3H) 1.50(m, 11H) 2.02(m, 1H) 0.95(dd, 6H) Aus- 9% 42% 25% 64% beute Schmp. 229 141 Masse 491(EI) 443(EI) 444(FAB)

Beispiel 135 136 137 138 Nr. 10.01(s, 1H) 9.70(s, 1H) 9.65(s, 1H) 9.70(s, 1H) 8.28(s, 1H) 8.11(s, 1H) 9.58(s, 1H) 8.10(s, 1H) 7.81(d, 2H) 7.90(d, 2H) 8.10(s, 1H) 7.89(d, 2H) 7.71(t, 1H) 7.64(d, 2H) 7.85(d, 2H) 7.63(d, 2H) 7.63(d, 2H) 7.35(t, 1H) 7.68(d, 2H) 7.39(t, 1H) 7.45(br, 1H) 6.55(d, 1H) 7.40(m, 2H) 6.68(d, 1H) 4.34(dt, 2H) 4.65(t, 1H) 7.18(m, 4H) 4.34(dd, 1H) 3.32(t, 2H) 4.45(m, 1H) 6.94(t, 1H) 3.36(m, 3H) 2.71(br, 2H) 3.53(m, 1H) 6.75(d, 1H) 2.25(q, 2H) 3.44(m, 6H) 4.40(m, 3H) 2.29(m, 1H) 2.75(q, 2H) 2.05(m, 1H) 1.05(dd, 6H) 1.20(d, 3H) 0.96(dd, 6H) Aus- 34% 53% 59% 57% beute Schmp. Masse 570(ES) 460(ES) 549(ES) 488(ES)

Beispiel 139 140 141 142 Nr. 9.82(s, 1H) 9.82(s, 1H) 9.58(s, 1H) 9.62(s, 1H) 8.15(s, 1H) 8.08(s, 1H) 8.12(s, 1H) 8.07(s, 1H) 7.82(d, 2H) 7.96(d, 2H) 7.83(d, 2H) 7.87(d, 2H) 7.64(d, 2H) 7.75(t, 1H) 7.68(d, 2H) 7.67(d, 2H) 7.39(t, 1H) 7.62(d, 2H) 7.15(s, 2H) 7.14(s, 2H) 6.55(d, 1H) 7.30(t, 1H) 5.92(s, 1H) 6.36(d, 1H) 4.64(t, 1H) 4.64(t, 1H) 5.28(t, 1H) 4.81(t, 1H) 4.50(t, 1H) 4.14(m, 2H) 3.50(d, 2H) 4.32(m, 1H) 3.65(s, 3H) 3.35(m, 2H) 1.42(s, 6H) 3.47(m, 2H) 3.4(m, 2H) 3.16(m, 1H) 1.52(m, 3H) 2.75(m, 2H) 2.75(q, 2H) 0.90(d, 3H) 2.35(m, 1H) 0.86(d, 3H) 1.00(dd, 6H) Aus- 20% 63% 23% 8% beute Schmp. Masse 502(ES) 382(ES) 415(EI) 443(EI)

Beispiel 143 144 145 78 Nr. 10.6(s, 1H) 10.11(s, 1H) 11.05(s, 1H) 9.69(s, 1H) 8.28(s, 1H) 8.45(s, 1H) 8.32(s, 1H) 8.06(s, 1H) 8.30(m, 5H) 7.86(d, 2H) 8.08(d, 1H) 7.88(d, 2H) 7.48(d, 1H) 7.78(d, 2H) 7.80(m, 4H) 7.63(d, 2H) 7.20(s, 1H) 7.15(br, 2H) 7.30(br, 2H) 7.18(s, 2H) 4.05(br, 1H) 5.32(m, 1H) 3.88(m, 1H) 7.10(t, 1H) 3.60(br, 2H) 3.91(m, 2H) 3.65(m, 1H) 6.65(d, 1H) 2.01(m, 1H) 3.53(m, 2H) 1.95(m, 2H) 4.47(m, 1H) 0.90(m, 6H) 2.05(m, 2H) 1.69(m, 2H) 3.97(m, 1H) 1.70(m, 2H) 1.35(m, 4H) 2.98(m, 2H) 2.00(m, 4H) 1.40(m, 8H) 0.85(t, 3H) Aus- 13% 47% 42% 20% beute Schmp. Masse 392(EI) 428(EI) 441(EI) 541(ES)

Beispiel 146 147 148 149 Nr. 11.13(s, 1H) 11.18(s, 1H) 11.15(s, 1H) 9.19(s, 1H) 8.38(s, 1H) 8.35(s, 1H) 8.35(s, 1H) 8.30(s, 1H) 7.92(d, 2H) 7.90(s, 4H) 7.90(d, 2H) 8.02(s, 1H) 7.75(m, 3H) 7.62(d, 1H) 7.65(m, 3H) 7.62(m, 1H) 4.04(m, 1H) 4.02(m, 1H) 4.01(m, 1H) 6.85(d, 1H) 3.80(s, 3H) 3.62(m, 2H) 3.60(m, 6H) 6.05(d, 1H) 3.65(m, 2H) 3.02(s, 3H) 2.85(m, 4H) 4.03(m, 1H) 2.00(m, 1H) 2.00(m, 1H) 2.00(m, 1H) 3.56(m, 2H) 0.96(d, 3H) 0.95(d, 3H) 0.95(d, 3H) 1.96(m, 1H) 0.89(d, 3H) 0.89(d, 3H) 0.85(d, 3H) 0.97(d, 3H) 0.90(d, 3H) Aus- 86% 33% 79% 42% beute Schmp. 225 211 232 241 Masse 408(EI) 428(EI) 501(EI) 411(ES)

Beispiel 150 151 152 153 Nr. 11.19(s, 1H) 10.96(s, 1H) 9.50(s, 1H) 12.90(s, 1H) 10.80(s, 1H) 8.35(s, 1H) 8.08(s, 1H) 9.45(s, 1H) 8.30(m, 2H) 7.95(m, 2H) 7.75(m, 5H) 8.52(s, 1H) 7.85(d, 1H) 7.65(m, 3H) 6.17(d, 1H) 8.05(s, 1H) 7.72(d, 1H) 4.04(m, 1H) 4.80(br, 1H) 7.82(d, 1H) 7.20(d, 1H) 3.62(m, 2H) 4.64(br, 2H) 7.50(d, 1H) 4.02(m, 1H) 2.00(m, 1H) 4.05(m, 1H) 7.32(t, 1H) 3.60(m, 2H) 0.90(M, 6H) 3.94(m, 1H) 6.11(d, 1H) 2.00(m, 1H) 3.52(m, 6H) 4.72(s, 1H) 1.01(d, 3H) 2.01(m, 1H) 4.10(s, 1H) 0.90(d, 3H) 0.93(dd, 6H) 3.60(m, 2H) 2.01(m, 1H) 0.99(d, 3H) 0.92(d, 3H) Aus- 27% 65% 85% 9% beute Schmp. 231 Masse 420(ES) 395(ES) 468(ES) 395(ES)

Beispiel 154 155 156 157 Nr. 10.91(s, 1H) 11.05(s, 1H) 10.51(s, 1H) 15.5o(s, 1H) 8.38(s, 1H) 8.34(m, 2H) 8.22(s, 1H) 9.50(s, 1H) 7.90(d, 1H) 7.75(m, 3H) 7.71(d, 1H) 8.40(s, 1H) 7.80(m, 4H) 7.52(t, 1H) 7.27(m, 1H) 8.11(s, 1H) 7.05(d, 1H) 4.04(m, 1H) 6.86(m, 2H) 7.80(d, 1H) 4.50(s, 2H) 3.85(s, 3H) 6.06(s, 2H) 7.53(d, 1H) 4.04(m, 1H) 3.65(m, 2H) 3.96(m, 1H) 6.16(d, 1H) 3.62(m, 2H) 2.00(m, 1H) 3.62(m, 2H) 4.78(br, 1H) 1.96(m, 1H) 0.94(d, 3H) 1.99(m, 1H) 4.03(m, 1H) 0.93(d, 3H) 0.85(d, 3H) 0.90(m, 6H) 3.60(m, 2H) 0.85(d, 3H) 2.01(m, 1H) 0.91(dd, 6H) Aus- 90% 48% 77% 21% beute Schmp. 170 181 177 196 Masse 381(ES) 409(ES) 394(EI) 391(EI)

Diastereomere1/2(ca. 1:3)

Diastereomere1/2(ca. 6:1)

Beispiel 158 159* 160* 161* Nr. 10.80(s, 1H) 9.65 9.65 7.92(s, 1H) 8.31(s, 1H) (s, 1H, 1 + 2) (s, 1H, 1 + 2) 7.84(d, 2H) 7.97(d, 2H) 8.08 8.08 7.58(d, 2H) 7.88(m, 3H) (s, 1H, 1 + 2) (s, 1H, 1 + 2) 3.72(m, 1H) 7.52(m, 5H) 7.88 7.88 3.35(m, 2H) 4.01(m, 1H) (d, 2H, 1 + 2) (d, 2H, 1 + 2) 3.10(m, 1H) 3.62(m, 2H) 7.65 7.65 2.91(m, 2H) 2.00(m, 1H) (d, 2H, 1 + 2) (d, 2H, 1 + 2) 2.00(m, 2H) 0.91(m, 6H) 7.15 7.15 1.89(m, 2H) (s, 1H, 1 + 2) (s, 1H, 1 + 2) 1.66(m, 4H) 6.62(d, 1H, 2) 6.62(d, 1H, 2) 1.39(m,5H) 6.40(d, 1H, 1) 6.40(d, 1H, 1) 4.05(m, 1H, 1) 4.05(m, 1H, 1) 3.89(m, 1H, 2) 3.89(m, 1H, 2) 2.30-1.20 2.30-1.20 (m, 15H, 1 + 2) (m, 15H, 1 + 2) Aus- 37% 21% 14% 8% beute Schmp. 199 >300 Masse 469(EI) 468(EI) 468(EI) 508(EI)

Diastereomere1/2(ca. 1:1)

Bsp.-Nr. 162 163* 164 165 11.25(s, 1H) 10.95(s, 1H) 9.65(s, 1H) 9.40(s, 1H) 10.72(s, 1H) 8.54(s, 1H) 8.47(s, 1H) 9.47(br, 2H) 8.10(s, 1H) 8.29(s, 1H) 9.30(br, 2H) 7.82(d, 1H) 7.63(s, 1H) 8.32(2xs, 2H) 7.45(m, 2H) 7.43(d, 1H) 8.08(d, 1H) 6.20(d, 1H) 7.07(m, 3H) 7.88(d, 2H) 4.70(t, 1H) 4.06(m, 1H) 7.75(m, 6H) 4.10(m, 1H) 3.63(m, 2H) 7.30(br, 4H) 3.60(m, 2H) 1.98(m, 1H) 6.95(d, 1H) 3.15(s, 3H) 0.95(d, 3H) 4.12(m, 1H) 2.00(m, 1H) 0.85(d, 3H) 3.98(m, 1H) 0.96(d, 3H) 3.30(m, 1H) 0.89(d, 3H) 3.10(m, 1H) 2.69(m, 2H) 2.25(m, 2H) 1.80(m, 18H) 1.01(m, 4H) 0.72(m, 4H) Aus- 16% 33% 14% 51% beute Schmp. 195 162-164 Masse 446(ES) 480(EI) 429(ES) 462(EI)

Diastereomere1/2(ca. 1:1)

Beispiel 166 167* 168* 169 Nr. 10.90(s, 1H) 11.15(br, 1H) 11.30(br, 2H) 9.05(br, 1H) 8.95(s, 1H) 10.90(s, 1H) 11.08(s, 1H) 8.85(s, 1H) 7.93(m, 2H) 9.75(br, 2H) 10.92(s, 1H) 8.11(d, 1H) 7.25(m, 3H) 8.35(s, 1H) 9.90(s, 1H) 7.97(s, 1H) 6.30(s, 1H) 7.78(m, 4H) 9.70(s, 1H) 7.47(dd, 1H) 6.00(d, 1H) 7.30(br, 2H) 8.36(2xs, 2H) 6.80(d, 1H) 4.75(tr, 1H) 4.15(m, 1H) 8.20(d, 1H) 5.95(d, 1H) 4.05(m, 1H) 3.50(m, 5H) 7.93(d, 2H) 4.80(br, 2H) 3.60(m, 2H) 2.85(s, 6H) 7.75(m, 6H) 3.90(m, 2H) 2.00(m, 1H) 1.90(m, 8H) 7.35(br, 4H) 3.45(m, 6H) 1.00(m, 6H) 7.10(d, 1H) 2.00(m, 1H) 4.15(m, 1H) 0.90(m, 6H) 3.98(m, 1H) 3.64(m, 8H) 3.40(m, 5H) 3.10(m, 5H) 1.95(m, 26H) Aus- 6% 16% 58% 60% beute Schmp. 256 261 Masse 390(ES) 512(ES) 538(ES) 484(ES)

Diastereomere1/2(ca. 1:1)

Beispiel 170* 171 172 173 Nr. 11.05(s, 1H) 10.45(s, 1H) 11.05(s, 1H) 8.90(s, 1H) 10.90(s, 1H) 8.25(s, 1H) 8.35(m, 2H) 8.72(s, 1H) 10.6(br, 2H) 8.00(br, 1H) 7.82(d, 1H) 7.95(s, 1H) 8.35(2xs, 2H) 7.85(d, 2H) 7.65(d, 2H) 7.18(m, 1H) 8.15(d, 1H) 7.75(d, 2H) 7.50(t, 1H) 7.05(dd, 1H) 7.80(m, 8H) 7.45(br, 1H) 4.05(m, 1H) 6.75(d, 1H) 7.30(br, 4H) 3.60(m, 5H) 3.62(m, 2H) 5.99(d, 1H) 7.05(m, 1H) 3.35(m, 2H) 2.00(m, 1H) 4.74(t, 1H) 4.25(m, 1H) 2.80(m, 2H) 0.96(d, 3H) 4.03(m, 1H) 3.95(m, 2H) 2.41(t, 2H) 0.85(d, 3H) 3.70(s, 3H) 3.65(m, 1H) 1.90(m, 2H) 3.60(m, 2H) 3.20(m, 10H) 2.00(m, 1H) 1.90(m, 24H) 0.90(m, 6H) Aus- 64% 7% 65% 40% beute Schmp. 226 164 206 144 Masse 525(ES) 488(ES) 395(ES) 397(ES)

Diastereomere1/2(ca. 1:1)

Diastereomere3/4(ca. 1:1)

Beispiel 174* 175* 176 177 Nr. 11.05(m, 3H) 11.15(br, 1H) 8.00(s, 1H) 9.65(s, 1H) 10.48(s, 1H) 11.05(s, 2H) 7.80(m, 4H) 8.08(s, 1H) 8.38(s, 2H) 10.65(br, 1H) 4.48(m, 1H) 7.85(d, 2H) 7.80(m, 8H) 8.30(s, 2H) 3.65(d, 2H) 7.65(d, 2H) 7.80(br, 4H) 8.13(m, 2H) 1.75(m, 1H) 7.40(br, 1H) 7.10(s, 1H) 7.88(m, 8H) 1.59(m, 2H) 7.15(s, 2H) 6.95(s, 1H) 7.30(br, 4H) 1.01(d, 3H) 3.55(m, 2H) 4.42(m, 2H) 4.40(m, 2H) 0.92(d, 3H) 2.55(m, 2H) 4.18(m, 2H) 4.00(br, 2H) 2.15(m, 2H) 3.70-2.90 3.70-2.90 1.80(m, 3H) (m, 10H) (m, 10H) 1.65(m, 1H) 2.40-1.60 2.40-1.40 (m, 20H) (m, 20H) Aus- 95% 51% 3% 8% beute Schmp. Masse 511(ES) 511(ES) 443(EI) 456(EI)

Beispiel 178 179 180 181 Nr. 9.49(s, 1H) 9.61(s, 1H) 9.65(s, 1H) 9.71(s, 1H) 8.25(s, 1H) 8.08(s, 1H) 8.11(s, 1H) 8.06(s, 1H) 7.80(m, 4H) 7.88(d, 2H) 7.81(s, 2H) 7.90(d, 2H) 7.32(br, 2H) 7.65(d, 2H) 7.63(d, 2H) 7.61(d, 2H) 4.03(m, 2H) 7.60(t, 1H) 7.15(s, 2H) 7.37(t, 1H) 3.75(m, 1H) 7.15(s, 2H) 6.64(d, 1H) 6.56(d, 1H) 3.35(m, 2H) 3.45(m, 2H) 4.28(m, 3H) 4.66(m, 2H) 1.80(m, 2H) 2.40(t, 2H) 2.00(m, 1H) 3.90(m, 1H) 1.40(m, 2H) 2.20(s, 6H) 1.98(s, 3H) 3.39(m, 3H) 1.75(t, 2H) 0.98(d, 3H) 2.78(q, 2H) 0.93(d, 3H) 1.96(m, 4H) 1.56(m, 2H) 1.29(m, 2H) Aus- 17% 9% 27% 24% beute Schmp. Masse 427(EI) 428(EI) 472(ES) 486(ES)

Beispiel 182 183 184 185 Nr. 9.68(s, 1H) 10.97(s, 1H) 11.06(s, 1H) 11.01(s, 1H) 9.47(s, 1H) 8.30(s, 1H) 8.04(m, 1H) 8.38(s, 1H) 8.10(s, 1H) 8.02(d, 1H) 7.82(m, 2H) 7.82(s, 4H) 7.81(d, 2H) 7.81(m, 4H) 7.70(m, 2H) 7.40(d, 1H) 7.67(d, 2H) 7.30(s, 2H) 7.30(s, 2H) 7.32(s, 2H) 7.14(s, 2H) 4.14(m, 1H) 6.72(m, 1H) 4.20(m, 1H) 6.76(m, 3H) 1.80(m, 12H) 3.75(m, 5H) 3.70(m, 2H) 4.47(m, 2H) 1.88(m, 2H) 0.97(s, 9H) 4.30(m, 1H) 1.48(m, 2H) 3.65(s, 6H) 3.54(s, 3H) 1.99(m, 1H) 0.98(d, 3H) 0.92(d, 3H) Aus- 57% 78% 26% 76% beute Schmp. Masse 639(ES) 439(EI) 348(EI) 445(EI)

Beispiel 186 187 188 189 Nr. 9.71(s, 1H) 7.75(s, 1H) 10.60(s, 1H) 11.19(s, 1H) 8.11(s, 1H) 7.65(d, 2H) 8.29(s, 1H) 8.03(d, 1H) 7.90(d, 2H) 7.58(d, 2H) 7.79(d, 2H) 7.88(d, 2H) 7.70(d, 2H) 5.82(s, 1H) 7.71(d, 2H) 7.78(d, 2H) 7.12(s, 2H) 4.25(s, 2H) 7.28(s, 2H) 7.31(s, 2H) 6.75(d, 1H) 3.40(t, 2H) 6.60(s, 1H) 6.58(d, 1H) 4.45(m, 1H) 2.82(t, 2H) 3.58(s, 2H) 3.60(m, 4H) 2.25(m, 6H) 2.06(s, 3H) 2.10(m, 2H) 1.20(m, 6H) 1.90(m, 2H) 1.78(m, 2H) 1.55(m, 4H) Aus- 16% 7% 61% 35% beute Schmp. Masse 440(ES) 480(ES) 443(EI) 321(EI)

Diastereomer 1

Diastereomer 2

Beispiel 190 191* 192* 193 Nr. 10.61(s, 1H) 9.67(s, 1H) 9.63(s, 1H) 10.61(s, 1H) 8.28(s, 1H) 8.08(s, 1H) 8.06(s, 1H) 8.28(s, 1H) 7.82(d, 2H) 7.88(d, 2H) 7.85(d, 2H) 7.78(m, 4H) 7.73(d, 2H) 7.65(d, 2H) 7.65(d, 2H) 7.45(d, 1H) 7.53(br, 1H) 7.11(s, 2H) 7.15(s, 2H) 7.20(s, 2H) 7.25(s, 2H) 6.35(d, 1H) 6.55(d, 1H) 4.30(br, 2H) 4.25(m, 1H) 4.10(m, 1H) 3.95(m, 1H) 3.53(m, 2H) 2.59(br, 1H) 3.62(m, 4H) 3.58(m, 4H) 1.21(d, 3H) 2.21(br, 1H) 2.45(m, 4H) 2.50(m, 4H) 1.94(m, 1H) 2.19(m, 1H) 1.96(m, 1H) 1.40(m, 7H) 1.88(m, 4H) 1.50(m, 4H) 1.65(m, 4H) 1.30(m, 4H) Aus- 63% 15% 17% 57% beute Schmp. Masse 437(EI) 511(ES) 511(EI) 403(EI)

Beispiel 194 195 196 197 Nr. 9.89(s, 1H) 10.98(s, 1H) 10.39(s, 1H) 10.85(s, 1H) 8.21(s, 1H) 8.51(br, 1H) 8.30(s, 1H) 8.71(d, 1H) 7.82(d, 2H) 8.29(s, 1H) 8.04(d, 2H) 8.31(s, 1H) 7.65(m, 3H) 7.81(m, 4H) 7.70(d, 2H) 7.72(d, 2H) 7.17(br, 2H) 7.29(br, 2H) 7.21(br, 2H) 7.55(d, 2H) 4.30(m, 2H) 3.45(m, 4H) 6.55(s, 1H) 7.30(m, 6H) 1.68(m, 2H) 3.49(s, 1H) 5.41(m, 1H) 1.45(m, 2H) 2.32(m, 2H) 3.49(m, 2H) 1.85(m, 2H) 2.11(m, 2H) 1.60(m, 5H) 1.29(m, 1H) Aus- 26% 56% 12% 61% beute Schmp. Masse 476(EI) 417(EI) 450(EI) 479(EI)

(+)-Enantiomer

(−)-Enantiomer

Diastereomer 1

Diastereomer 2 Beispiel 198 199 200 201 Nr. 11.01(s, 1H) 11.01(s, 1H) 9.16(s, 1H) 8.32(s, 1H) 8.32(s, 1H) 8.07(s, 1H) 8.10(d, 1H) 8.10(d, 1H) 7.89(d, 2H) 7.80(m, 4H) 7.80(m, 4H) 7.67(d, 2H) 7.30(br, 2H) 7.30(br, 2H) 7.15(s, 2H) 3.70(m, 1H) 3.70(m, 1H) 6.45(d, 1H) 1.80(m, 5H) 1.80(m, 5H) 4.35(s, 2H) 1.48(m, 1H) 1.48(m, 1H) 3.97(m, 1H) 1.29(m, 2H) 1.29(m, 2H) 3.40(m, 4H) 1.07(m, 1H) 1.07(m, 1H) 2.85(m, 1H) 0.83(d, 3H) 0.83(d, 3H) 2.55(m, 1H) 1.82(m, 2H) 1.61(m, 6H) Aus- 4% 4% 7% 2% beute Schmp. Masse 439(EI) 439(EI) 515(ES) 515(ES)

Diastereomer 1

Diastereomer 2

Beispiel 202 203* 204* 205 Nr. 10.21(s, 1H) 9.66(s, 1H) 9.73(s, 1H) 8.18(s, 1H) 8.08(s, 1H) 8.11(s, 1H) 8.10(d, 2H) 7.90(d, 2H) 7.82(d, 2H) 7.92(d, 2H) 7.69(d, 2H) 7.65(d, 2H) 6.39(d, 1H) 7.15(s, 2H) 7.12(s, 2H) 4.80(br, 1H) 6.53(d, 1H) 6.80(d, 1H) 4.05(m, 1H) 3.93(m, 1H) 4.67(m, 1H) 3.62(m, 2H) 2.05(m, 5H) 3.13(m, 1H) 2.00(m, 1H) 1.51(m, 2H) 2.86(m, 3H) 0.99(d, 3H) 1.15(m, 2H) 2.18(m, 2H) 0.92(d, 3H) 0.42(m, 2H) 0.25(m, 2H) Aus- 10% 2% 2% 16% beute Schmp. Masse 483(ES) 480(EI) 480(EI) 430(ES)

Beispiel 206 207 208 209 Nr. 9.75(s, 1H) 10.98(s, 1H) 11.00(s, 1H) 9.55(s, 1H) 8.19(s, 1H) 8.50(d, 2H) 8.31(s, 1H) 8.08(s, 1H) 7.75(d, 2H) 8.31(s, 1H) 7.74(m, 5H) 7.80(d, 2H) 7.18(d, 2H) 7.97(d, 2H) 7.21(d, 1H) 7.60(d, 2H) 7.17(s, 2H) 7.78(d, 2H) 6.80(d, 1H) 6.58(br, 4H) 6.68(d, 1H) 7.57(d, 1H) 4.00(m, 1H) 6.20(d, 1H) 5.35(t, 1H) 7.00(t, 1H) 3.62(m, 2H) 4.80(br, 1H) 4.71(m, 1H) 4.01(m, 1H) 1.95(m, 1H) 4.04(m, 1H) 3.91(m, 2H) 3.62(m, 2H) 0.98(d, 3H) 3.60(m, 2H) 3.65(s, 3H) 1.97(m, 1H) 0.90(d, 3H) 2.00(m, 1H) 0.98(d, 3H) 0.99(d, 3H) 0.92(d, 3H) 0.92(d, 3H) Aus- 5% 55% 44% 77% beute Schmp. 223 248 228 231 Masse 446(ES) 507(EI) 514(EI)

Beispiel 210 211 Nr. 10.03(s, 1H) 10.90(s, 1H) 8.38(s, 1H) 8.40(m, 1H) 8.14(s, 1H) 8.30(s, 1H) 7.81(d, 2H) 7.88(d, 2H) 7.60(d, 1H) 7.73(d, 2H) 7.30(m, 7H) 7.38(br, 1H) 4.99(s, 2H) 3.45(m, 4H) 3.42(m, 2H) 2.38(s, 3H) 2.97(m, 2H) 1.62(m, 2H) 1.58(m, 2H) 1.45(m, 2H) 1.30(m, 4H) Aus- 86% 22% beute Schmp. Masse 528(Cl) 429(EI)

Beispiel 212 71 Nr. 9.18(s, 1H) 9.66(s, 1H) 9.05(s, 1H) 8.08(s, 1H) 7.98(s, 1H) 7.88(d, 2H) 7.18(m, 2H) 7.63(m, 3H) 6.98(m, 2H) 7.28(t, 1H) 6.31(m, 1H) 7.11(s, 2H) 4.45(t, 1H) 6.88(s, 1H) 3.47(m, 4H) 3.65(m, 2H) 1.63(m, 2H) 2.88(t, 2H) 1.48(m, 2H) Aus- 41% 77% beute Schmp. Masse 352(EI) 437(EI)

Beispiel 213 61 214 215 Nr. 12.40(br, 1H) 12.41(br, 1H) 8.03(s, 1H) 9.55(s, 1H) 11.10(s, 1H) 11.11(s, 1H) 7.76(m, 4h) 8.10(s, 1H) 8.08(d, 2H) 8.10(d, 1H) 3.70(s, 2H) 7.80(d, 2H) 7.79(m, 4H) 7.80(m, 5H) 1.92(m, 4H) 7.68(d, 2H) 7.30(s, 2H) 7.30(s, 2H) 0.92(m, 6H) 7.15(s, 2H) 4.04(m, 1H) 4.08(m, 1H) (in MeOD) 5.82(s, 1H) 3.60(m, 2H) 3.63(m, 2H) 3.74(d, 1H) 2.07(s, 3H) 2.50(m, 2H) 3.52(d, 1H) 2.00(m, 1H) 2.01(m, 1H) 2.72(m, 1H) 0.97(d, 3H) 1.15(t, 3H) 1.35(s, 3H) 0.90(d, 3H) 0.99(d, 3H) 0.97(d, 3H) 0.92(d, 3H) 0.91(d, 3H) Aus- 49% 25% 2% 9% beute Schmp. Masse 365(EI) 379(EI) 443(ES) 444(ES)

Beispiel 216 217 218 219 Nr. 10.88(s, 1H) 10.88(s, 1H) 11.01(s, 1H) 11.11(s, 1H) 8.36(s, 1H) 8.36(s, 1H) 8.52(br, 1H) 8.53(m, 1H) 8.03(d, 1H) 8.03(d, 1H) 8.29(s, 1H) 8.36(s, 1H) 7.79(m, 4H) 7.79(m, 4H) 7.78(m, 4H) 7.80(m, 4H) 7.28(br, 2H) 7.28(br, 2H) 7.32(s, 2H) 7.31(s, 2H) 4.65(m, 1H) 4.65(m, 1H) 3.39(m, 2H) 3.71(m, 2H) 3.89(m, 2H) 3.89(m, 2H) 1.70(m, 6H) 2.65(m, 2H) 3.71(m, 2H) 1.15(m, 3H) 2.19(m, 2H) 0.96(m, 2H) Aus- 65% 34% 58% 88% beute Schmp. 239 239 238 280 Masse 439(EI) 413(EI) 439(EI) 416(EI)

Beispiel 74 56 220 221 Nr. 9.67(s, 1H) 9.70(s, 1H) 8.92(m, 1H) 9.66(s, 1H) 8.11(s, 1H) 8.81(m, 1H) 8.08(s, 1H) 7.88(m, 4H) 7.96(s, 1H) 7.83(d, 2H) 6.25(d, 1H) 7.43(d, 2H) 7.68(d, 2H) 4.81(m, 1H) 6.67(d, 2H) 7.22(t, 1H) 4.05(m, 1H) 6.20(m, 1H) 7.11(s, 2H) 3.61(m, 2H) 4.38(m, 1H) 3.95(m, 4H) 2.01(m, 1H) 3.48(m, 1H) 3.48(m, 2H) 0.97(d, 3H) 3.37(m, 1H) 1.79(m, 4H) 0.92(d, 3H) 1.20(d, 3H) 1.18(t, 6H) Aus- 7% 17% 65% 19% beute Schmp. 285 158 166 Masse 457(EI) 392(EI) 354(EI) 522(ES)

Beispiel 222 223 224 225 Nr. 9.81(s, 1H) 9.71(s, 1H) 9.70(s, 1H) 10.29(s, 1H) 9.08(s, 1H) 8.13(s, 1H) 8.08(s, 1H) 8.83.(m, 2H) 8.68(s, 1H) 7.89(d, 2H) 7.88(d, 2H) 8.51(m, 1H) 8.35(m, 1H) 7.66(d, 2H) 7.65(d, 2H) 8.26(s, 1H) 8.20(s, 1H) 7.31(t, 1H) 7.25(m, 3H) 7.93(d, 2H) 8.02(t, 1H) 7.14(s, 2H) 6.11(m, 1H) 7.60(d, 2H) 7.63(m, 5H) 3.98(m, 2H) 3.40(m, 5H) 7.51(d, 2H) 7.17(s, 2H) 3.69(s, 3H) 7.25(br, 2H) 7.03(s, 1H) 3.64(s, 3H) 4.90(d, 2H) 4.82(d, 2H) Aus- 54% 23% 7% 43 beute Schmp. 300 300 243 Masse 501(EI) 465(EI) 434(EI)

Beispiel 226 227 228 229 Nr. 10.38(s, 1H) 10.30(s, 1H) 10.52(s, 1H) 10.88(s, 1H) 8.52(br, 1H) 8.78(m, 1H) 8.66(m, 1H) 8.92(m, 1H) 8.23(s, 1H) 8.36(m, 3H) 8.28(s, 1H) 8.33(s, 1H) 7.72(m, 4H) 7.81(m, 2H) 7.63(m, 4H) 7.72(d, 2H) 7.36(m, 1H) 7.60(m, 4H) 7.26(m, 6H) 7.62(d, 2H) 7.22(s, 2H) 7.22(br, 2H) 4.63(d, 2H) 7.30(m, 4H) 7.03(m, 1H) 4.94(d, 2H) 6.89(d, 2H) 6.95(m, 1H) 4.62(d, 2H) 4.80(d, 2H) 3.70(s, 3H) Aus- 47% 41% 88% 89% beute Schmp. 229 1287 259 233 Masse 440(CI) 434(EI) 451(EI) 463(EI)

Beispiel Nr. 230 10.45(s, 1H) 8.20(s, 1H) 8.05(m, 1H) 7.79(m, 4H) 7.21(s, 2H) 3.50(m, 2H) 1.83(m, 2H) 1.56(m, 2H) Ausbeute 58% Schmp. >300 Masse 466(ES)

Beispiel 231 232 233 234 Nr. 10.3(s, 1H) 9.28(s, 1H) 10.48(s, 1H) 9.63(s, 1H) 8.34(tr, 1H) 8.0(s, 1H) 8.25(s, 1H) 8.12(s, 1H) 8.2(s, 1H) 7.73(d, 2H) 7.85(m, 4H) 7.65(m, 4H) 7.9(m, 4H) 7.63(tr, 1H) 7.25(m, 1H) 7.42(d, 2H) 4.3(q, 2H) 7.18(d, 2H) 7.15(s, 1H) 7.35(tr, 2H) 4.2(m, 2H) 5.0(m, 1H) 5.1(m, 1H) 7.21(m, 1H) 3.23(tr, 1H) 4.3(s, 2H) 3.58(m, 4H) 7.16(s, 1H) 1.32(tr, 3H) 4.14(m, 2H) 5.35(m, 1H) 3.11(tr, 1H) 1.55(d, 3H) Aus- 85% 35% 33% 25% beute Schmp. Masse 330(EI) 288(EI) 389(Cl) 448(ESI)

Beispiel- 235 236 237 238 Nr. Schmp. [° C.] Masse 486(ES) 516(ES) 504(ES) 488(ES)

Beispiel- 239 240 241 242 Nr. Schmp. [° C.] Masse 536(ES) 502(ES) 484(ES) 551(ES)

Beispiel- 243 244 245 Nr. Schmp. [° C.] Masse 516(ES) 514(ES) 433(ES)

Beispiel- 246  247 248 249 Nr. Schmp. 205 >300 [° C.] Masse 446(ES) 415(EI) 504(ES)  431(ES)

Beispiel- 250 251 252 253 Nr. Schmp. 113 231 187 [° C.] Masse 488(ES) 446(ES) 433(ES)

Nr. 254 255 256 257 Schmp. [° C.] Masse 399(ES) 444(ES) 474(ES) 486(ES)

Compounds Nos. 159, 160, 161, 163, 167, 168, 170, 174, 175, 191, 192, 203 and 204 that are identified with *) can be produced by the process variants that are described under Example No. 292.

EXAMPLE 258 Production of 4-(5-bromo-4-morpholin-4-yl-pyrimidin-2-ylamino)-phenylsulfonamide

202 mg (0.60 mmol) of the compound of Example No. 122 is mixed with 1 ml of water and 0.2 g (1.2 mmol) of bromine and stirred at room temperature. After 24 hours, 0.2 g (1.2 mmol) of bromine is added again, and it is stirred for another 24 hours at room temperature. The solvent is evaporated by means of underpressure, and the remaining residue is purified by chromatography (Flashmaster II, DCM/MeOH 7:3). 17 mg (0.04 mmol, 7%) of the product is obtained as a white solid.

Beispiel- 259 260 261 262 Nr. Schmp. 205-207 202-203 [° C.] Masse MS(ES) 452, 428(ES) 454(M + H, 100%)

Beispiel- Nr. Verbindung ESI-MS 263

434 264

434 265

477 266

477 267

552 268

552 269

Analogously to the process for the production of intermediate products that is described under Example 6.0, the following compounds were also produced:

Beispiel- 270 271 272 Nr.

Ausbeute 47% 90% Masse ESI: ESI: ESI: MH⁺ 480(100%) MH⁺ 432(100%) MH⁺ 446(18%) 478(97%) 430(94%) 115(30%) 157(43%)

Analogously to production example 1, the following compounds were also produced:

Beispiel- 273 274 275 276 Nr. Aus- 61% 44% 42% 68% beute Masse EI: EI: ESI: EI: M⁺ 463(4%) M⁺ 403(24%) MH⁺ 418 M⁺ 401(33%) 277(8%) 358(100%) 100% 372(100%) 105(100%) 277(52%) 416(94%) 344(38%) 346(8%)

Beispiel- 277 278 279 280 Nr. Aus- 81% 58% 20% 30% beute Masse EI: ESI: ESI: ESI: M⁺ 431(5%) MH⁺ 444(100%) MH+ 494(75%) MH+ 418(100%) 372(100%) 442(97%) 346(18%) 416(97%) 291(46%) 115(20%) 214(55%) 310(27%)

Beispiel- 281 282 283 284 Nr. Aus- 55% 43% ~18% 35% beute Masse ESI: ESI: ESI: ESI: MH⁺ 444(100%) MH⁺ 446(100%) MH⁺ 416(100%) MH⁺ 446(100%) 442(97%) 444(95%) 414(96%) 444(90%) 214(12%) 346(5%) 317(4%)

Beispiel- 285 286 287 288 Nr. Aus- 51% 46% 47% 61% beute Masse ESI: ESI: ESI ESI MH⁺ 520(100%) MH⁺ 520(100%) MH⁺ 432(100%) MH⁺ 446(100%) 518(97%) 518(97%) 430(95%) 444(93%) 115(27%) 115(23%) 346(5%) 115(13%)

According to the production variants below, the following compounds are also synthesized:

30 mg (0.0678 mmol) of compound No. 278 is dissolved in 1 ml of methanol/tetrahydrofuran 1:1. After adding ≈10 mg of sodium borohydride, stirring is continued for 2 hours. Then, it is quenched with ≈3-4 drops of glacial acetic acid while being cooled, and it is concentrated by evaporation. Below, the crude product is taken up with a little water, suctioned off, rewashed with acetonitrile and dried in a vacuum at 60° C. Yield: 21 mg (70% of theory) of the desired compound.

Beispiel- 289 290 Nr. Aus- 52% 70% beute Masse EI: ESI: M⁺ 465(5%) MH⁺ 446(100%) 358(40%) 444(93%) 207(31%) 117(20%)

EXAMPLE 291 Production of the Oxime Ether-Pyrimidine Compounds of General Formula I

The production of the oxime ether is carried out according to the following general reaction diagram:

R⁸ and R⁹ have the meanings that are indicated in general formula I.

Production of Example 291

50 mg (0.12 mmol) of compound No. 283, 34 mg of hydroxylammonium chloride and 150 mg of pulverized KOH are refluxed for 2 hours in 2 ml of ethanol. Then, it is poured onto ice water and acidified with glacial acetic acid, extracted 3 times with dichloromethane/isopropanol 4:1, dried with magnesium sulfate and concentrated by evaporation. The residue is suspended with acetonitrile, suctioned off and dried at 60° C. Yield: 28 mg (54% of theory) of the desired compound.

Mass

ESI:

MH⁺ 429 (29%)

371 (61%)

289 (91%)

Similarly produced were also the following compounds:

Besispiel- 292 293 294 Nr. Ausbeute 34% 36% 40% Masse ESI: ESI: ESI: MH+ 443(95%) MH+ 485(92%) MH⁺ 487(91%) 445(99%) 487(99%) 489(89%) 373(32%) 373(32%)

EXAMPLE 295 Reduced Amination

50 mg (0.12 mmol) of compound No. 283 and 7.5 mg (0.132 mmol) of cyclopropylamine are dissolved in 2 ml of 1,2-dichloroethane. After 9.1 mg (0.144 mmol) of sodium cyanoborohydride is added, it is allowed to stir for 12 more hours. Then, it is diluted with dichloromethane/isopropanol 4:1, washed 2× with water, dried with magnesium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel with dichloromethane/methanol 95:5. Yield: 18 mg (33% of theory) of the desired compound.

Aus- 33% beute Masse ESI: MH⁺ 457(98%) 455(93%) 249(55%)

Produced similarly are also compounds Nos. 159, 160, 161, 163, 167, 168, 170, 174, 175, 191, 192, 203 and 204.

EXAMPLES 296 AND 297

Produced similarly to Example 1 are also the following two compounds:

Beispiel 296 297 Ausbeute 46% 47% Masse ESI: ESI: MH⁺ 432(30%) MH⁺ 446(45%) 434(31%) 448(49%) 123(100%) 123(90%)

Production of Sulfonamides of General Formula I

0.2 mmol of sulfonic acid fluoride is introduced into the reactor of a synthesizer. 1.0 ml of solvent, preferably 2-butanol, is added. 0.2 ml (0.2 mmol) of DMAP—dissolved in a solvent, for example DMSO or 2-butanol—and 0.2 ml (0.2 mmol) of the amine, dissolved in 2-butanol, are added in succession via a pipette. The reaction mixture is then stirred for 20 hours at 80° C. After the reaction is completed, the crude product is pipetted off, and the reactor is rewashed with 1.0 ml of THF. The solution of the crude product is then concentrated by evaporation and purified by HPLC.

The compounds below were produced:

[Key to Subsequent Tables:]

-   Beispiel-Nr.=Example No. -   Verbindung=Compound -   Molgewicht=Molecular Weight -   Schmelzpunkt=Melting point -   und=and

Beispiel- Nr. Verbindung Molgewicht ESI-MS 298

526,4968 526/528 299

562,5298 562/564 300

624,6006 624/626 301

501,4471 501/503 302

538,4682 538/540 303

588,4465 588/590 304

528,5126 528/530 305

542,5394 542/544 306

556,5662 556/558 307

570,593 570/572 308

510,4106 510/512 309

588,4465 588/590 310

548,503 548/550 311

555,4949 555/557 312

500,459 500/502 313

514,4858 514/516 314

515,4739 515/517 315

557,5543 557/559 316

470,3896 470/472 317

551,5069 551/553 318

534,4762 534/536 319

568,9213 568/570 320

524,4374 524/526 321

543,4839 543/545 322

488,4044 488/490 323

526,4776 526/528 324

564,502 564/566 325

527,4849 527/529 326

541,5117 541/543 327

538,4395 538/540 328

541,5117 541/543 329

521,4375 521/523 330

538,4395 538/540 331

521,4375 521/523 332

550,4752 550/552 333

550,4752 550/552 334

613,5551 613/615 335

534,4762 534/536 336

512,47 512/514 337

548,503 548/550 338

610,5738 610/612 339

487,4203 487/489 340

524,4414 524/526 341

574,4197 574/576 342

514,4858 516/514 343

528,5126 528/530 344

542,5394 542/544 345

556,5662 556/558 346

496,3838 496/498 347

574,4197 574/576 348

534,4762 534/536 349

541,4681 541/543 350

486,4322 486/488 351

500,459 500/502 352

501,4471 501/503 353

543,5275 543/545 354

456,3628 456/458 355

537,4801 537/539 356

520,4494 520/522 357

554,8945 554/556 358

510,4106 510/512 359

529,4571 529/531 360

474,3776 474/476 361

512,4508 541/514 362

550,4752 550/552 363

513,4581 513/515 364

527,4849 527/529 365

524,4127 524/526 366

527,4849 527/529 367

507,4107 507/509 368

524,4127 524/526 369

507,4107 507/509 370

536,4484 536/538 371

536,4484 536/538 372

599,5283 599/601 373

520,4494 520/522 374

512,47 512/514 375

548,503 548/550 376

610,5738 610/612 377

524,4414 524/526 378

574,4197 574/576 379

514,4858 514/516 380

528,5126 528/530 381

542,5394 542/544 382

496,3838 496/498 383

574,4197 574/576 384

534,4762 534/536 385

541,4681 541/543 386

486,4322 486/488 387

500,459 500/502 388

501,4471 501/503 389

543,5275 543/545 390

537,4801 537/539 391

520,4494 520/522 392

554,8945 554/556 393

510,4106 510/512 394

529,4571 529/531 395

474,3776 474/476 396

512,4508 512/514 397

513,4581 513/515 398

527,4849 527/529 399

524,4127 524/526 400

527,4849 527/529 401

507,4107 507/509 402

524,4127 524/526 403

507,4107 507/509 404

536,4484 526/538 405

536,4484 536/538 406

599,5283 599/601 407

520,4494 520/522 408

529,4419 529/531 409

534,4762 534/536 410

596,547 596/598 411

473,3935 473/475 412

510,4146 510/512 413

560,3929 560/562 414

500,459 500/502 415

514,4858 514/516 416

528,5126 528/530 417

482,357 482/484 418

560,3929 560/562 419

520,4494 520/522 420

527,4413 527/529 421

472,4054 472/474 422

486,4322 486/488 423

487,4203 487/489 424

529,5007 529/531 425

523,4532 523/525 426

506,4226 506/508 427

540,8677 540/542 428

496,3838 496/498 429

515,4303 515/517 430

460,3508 460/462 431

498,424 498/500 432

499,4313 499/501 433

513,4581 513/515 434

510,3859 510/512 435

513,4581 513/515 436

493,3839 493/495 437

510,3859 510/512 438

493,3839 493/495 439

522,4216 522/524 440

522,4216 522/524 441

585,5015 585/587 442

506,4226 506/508 443

515,4151 515/517 444

416,30 416/418

Production of the Pyrimidine-Sulfonyl Fluorides of General Formula I

The production of the pyrimidine-sulfonic acid fluorides is carried out analogously to the production of the sulfonic acid amides.

Beispiel-Nr. Verbindung Molgewicht Schmelzpunkt [° C.] und ESI-MS 445

405.25 217-220405/407 446

419.27 196-202419/421 447

419.27 165-196419/421 448

433.30 198-204433/435 449

433.30 144-149433/435 450

447.33 219-222447/449

Similarly produced to the above-described examples were also the following para-compounds:

Beispiel-Nr. Verbindung Molekular-gewicht ESI-MS 451

498.4432 498/500 452

534.4762 534/536 453

596.547 596/598 454

473.3935 473/475 455

510.4146 510/512 456

560.3929 560/562 457

500.459 500/502 458

514.4858 514/516 459

528.5126 528/530 460

542.5394 542/544 461

560.3929 560/562 462

520.4494 520/522 463

527.4413 527/529 464

472.4054 472/474 465

486.4322 486/488 466

529.5007 529/531 467

442.336 442/444 468

523.4532 523/525 469

506.4226 506/508 470

540.8677 540/542 471

496.3838 496/498 472

515.4303 515/517 473

460.3508 460/462 474

498.424 498/500 475

536.4484 536/538 476

499.4313 499/501 477

513.4581 513/515 478

510.3859 510/512 479

513.4581 513/515 480

493.3839 493/495 481

510.3859 510/512 482

493.3839 493/495 483

522.4216 522/524 484

522.4216 522/524 485

585.5015 585/587 486

506.4226 506/508 487

515.4151 515/517 488

512.47 512/514 489

548.503 548/550 490

610.5738 610/612 491

487.4203 487/489 492

524.4414 524/526 493

574.4197 574/576 494

514.4858 516/514 495

528.5126 528/530 496

542.5394 542/544 497

556.5662 556/558 498

496.3838 496/498 499

574.4197 574/576 500

543.4762 534/536 501

541.4681 541/543 502

486.4322 486/488 503

500.459 500/502 504

501.4471 501/503 505

543.5275 543/545 506

456.3628 456/458 507

537.4801 537/539 508

520.4494 520/522 509

566.4742 510

554.8945 554/556 511

510.4106 510/512 512

529.4571 529/531 513

474.3776 474/476 514

512.4508 512/514 515

550.4752 550/552 516

513.4581 513/515 517

527.4849 527/529 518

524.4127 524/526 519

527.4849 527/529 520

507.4107 507/509 521

524.4127 524/526 522

507.4107 507/509 523

536.4484 536/538 524

536.4484 536/538 525

599.5283 599/601 526

520.4494 520/522 527

529.4419 529/531

Separation of Diastereomer Mixtures of the Compounds According to the Invention Separation in the Example of the Diastereomer Mixture of Compound No. 275

[Key:]

-   Diastereomerengemisch=Diastereomer mixture -   Chirale HPLC=Chiral HPLC

The diastereomer mixture was separated in the two corresponding racemates (A and B) by means of HPLC. Conditions:

Column: Kromasil C18 (5 μm) 150 × 4.6 mm Eluant: 25% acetonitrile/water with 1 ml of NH3/1; Flow: 1.0 ml/min Detection: PDA 300 nm Retention times: Racemate A - 11.6 minutes Racemate B - 12.4 minutes

NMR DMSO-d6: DMSO-d6: 9.68, s, 1H 9.68, s, 1H 8.12, s, 1H 8.11, s, 1H 7.87, d, 2H 7.85, d, 2H 7.70, d, 2H 7.69, d, 2H 7.14, s, 2H 7.16, s, 2H 6.15, d, 1H 6.35, d, 1H 5.01, d, 1H 4.90, d, 1H 4.10, m, 1H 4.08, m, 1H 3.80, m, 1H 3.80, m, 1H 1.22, d, 3H 1.18, d, 3H 1.1, d, 3H 1.12, d, 3H

Below, racemates A and B in each case were separated by means of chiral HPLC.

Conditions: Column: Chiralpak AD (10 μm) 250 × 4.6 mm Eluant: Hexane/ethanol 80:20 Flow: 1.0 ml/min Detection: PDA 300 nm Retention times: Enantiomer A1 - 16.6 minutes Enantiomer A2 - 19.6 minutes Enantiomer B1 - 16.0 minutes Enantiomer B2 - 17.8 minutes

Production of the intermediate stages preferably used for the synthesis of the compounds of general formula I according to the invention.

EXAMPLE 1.0 Production of N-(2-chloro-5-fluoro-4-pyrimidinyl)-N-2-propynylamine

11.1 g (66 mmol) of 2,4-dichloro-5-fluoropyrimidine is dissolved in 60 ml of acetonitrile, and 10.2 ml (73 mmol) of triethylamine and 6.0 ml (86 mmol) of propynylamine are added. The reaction mixture is stirred overnight at room temperature and then poured into water. The mixture is extracted by means of ethyl acetate, the combined organic phases are dried on MgSO₂, and the solvent is evaporated by means of underpressure. After the remaining material is recrystallized with diisopropyl ether/hexane, the yield is 10.6 g (87% of theory) of the product.

5-H 8.18(3.3Hz, 1H) Solvent: DMSO 4CH 4.14(dd, 2H) Yield: 87% 3.20(t, 1H) Melting point: 96° C. NH 8.65(tb, 1H)

The 4-(diaminocyclohexyl) derivatives that are described below are synthesized via reductive aminations of the described keto derivative with use of triacetoxy borohydride (Abdel-Magid, Carson, Harris, Maryanoff, Sha, J. Org. Chem. 1996, 61, 3849). The keto derivative is obtained by TPAP oxidation (Griffith, Ley, Aldrichimica Acta 1990, 23, 13) of the corresponding alcohol.

Similarly produced are also the following intermediate compounds:

[Key to Subsequent Tables:]

-   Beispiel-Nr.=Example No. -   Lösemittel=Solvent -   Ausbeute=Yield -   Schmp.=Melting point -   Masse=Mass -   Chrom. Ausbeute=Chromatography yield

Beispiel-Nr. 1.1 1.2 1.3 1.4 Lösemittel CDCl₃ DMSO DMSO DMSO 5-H 7.87(s, 1H) 8.34(s, 1H) 8.24(s, 1H) 8.23(s, 1H) 4CH 4.32(dd, 2H) 4.48(q, 1H) 3.59(td, 2H) 3.21(t, 2H) 2.30(t, 1H) 1.93(dq, 2H) 2.78(t, 2H) 1.10(mc, 1H) 0.92(t, 3H) 7.57(s, 1H) 0.42(mc, 2H) 5CH 2.03(s, 3H) 3.66(s, 3H) 6.85(s, 1H) 0.37(mc, 2H) 7.90(tb, 1H) 7.84(t, 1H) NH 4.91(sb, 1H) 7.69(d, 1H) 11.92(sb, 1H) Ausbeute 80% 42% 33% 74% Schmp. 121-121.5° C. 73° C. 90° C. 98° C.

Beispiel-Nr. 1.5 1.6 1.7 1.8 Lösemittel DMSO DMSO DMSO DMSO 6-H 8.26(s, 1H) 8.26(s, 1H) 8.27(s, 1H) 8.37(s, 1H) 4CH 3.59(mc, 2H) 3.58(mc, 2H) 3.58(sb, 4H) 4.40(m, 1H) 3.90(mc, 1H) 3.97(mc, 1H) 4.14(mc, 1H) 3.49(dd, 1H) 1.98(mc, 1H) 1.96(mc, 1H) 3.33(dd, 1H) 0.94(d, 3H) 0.92(d, 3H) 3.26(s, 3H) 0.86(d, 3H) 0.84(d, 3H) 1.15(d, 3H) OH 4.67(mb, 1H) 4.74(t, 1H) 4.78(sb, 2H) NH 6.75(sb, 1H) 6.87(d, 1H) 6.73(sb, 1H) 7.29(d, 1H) Ausbeute 82% 91% 41% 74% Schmp. 113-114° C. 121-122° C. 155-156° C. Öl

Beispiel- 1.9 1.10 Nr. Lösemittel DMSO DMSO 6-H 8.24(s, 1H) 8.36(s, 1H) 4CH 3.49(q, 2H) 4.14(d, 2H) 2.50(t, 2H) 3.18(t, 1H) 2.42(t, 4H) 3.56(t, 4H) OH NH 7.57(sb, 1H) 8.40(s, 1H) Ausbeute 31% 73 Schmp. 118-119° C. 103-104° C.

Beispiel- 1.11 1.12 1.13 1.14 Nr. Löse- DMSO DMSO DMSO DMSO mittel 6-H 8.30(s, 1H) 8.32(s, 1H) 8.29(s, 1H) 8.24(s, 1H) 4.46(dq, 1H) 5.04(q, 1H) 3.7-3.9(2H) 4.25(m, 1H) 1.38(d, 3H) 2.39(m, 2H) 5.19(m, 1H) 3.48(m, 2H) 7.2-7.4(5H) NH 7.60(sb, 1H) 4.31(q, 1H) 7.72(d, 1H) 1.86(m, 2H) 5.09(t, 1H) OH 7.29(sb, 1H) 4.40(t, 1H) 2.43(m, 2H) 7.21(d, 1H) 8.13(d, 1H) 2.03(s, 3H) 7.13(d, 1H) 4.88(t, 1H) Aus- 87% 63% 99% 78% beute Schmp. 234° C. Zers. 210° C. Zers. 152-153° C. 130° C.

Beispiel-Nr. 1.15 1.16 1.17 Lösemittel DMSO DMSO DMSO 6-H 8.20(s, 1H) 8.21(s, 1H) 8.22(s, 1H) 3.55(m, 2H) 3.33(q, 2H) 3.39(q, 2H) 4.22(m, 1H) 1.53(m, 4H) 2.26(t, 2H) 5.03(m, 2H) 1.28(m, 2H) 1.79(q, 2H) 7.1-7.4(5H) 2.29(t, 2H) NH 6.53(d, 1H) 7.74(t, 1H) 7.78(t, 1H) 5.93(d, 1H) 12.11(sb, 1H) Ausbeute 93% 99% 11% Schmp. Öl Öl Öl

Beispiel-Nr. 1.18 1.19 1.20 Ausbeute 86% 64% 87% Masse ESI: ESI: Cl: MH⁺ 297(2%) MH⁺ 311(2%) M+ 354(100%) 266(22%) 248(20%) 352(72%) 234(30%) 236(18%) 308(54%)

Beispiel-Nr. 1.21 1.22 1.23 Ausbeute 26% ~20% 89% Masse EI: NMR, CDCl3 EI: M⁺ 327(10%) 8.16(s, 1H) M⁺ 265(15%) 222(36%) 6.55(s, 1H) 236(100%) 105(100%) 4.43(d, 2H) 209(18%) 1.29(s, 9H)

Beispiel-Nr. 1.24 1.25 1.26 Ausbeute 75% 70% 83% Masse Cl: Cl ESI: M⁺ 384(100%) M⁺ 384(100%) 319 3% 212(21%) 212(21%) 278 100% 91(7%) 91(7%) 220 68%

Beispiel-Nr. 1.27 Ausbeute 98% Masse ESI: MH⁺ 296(90%) 298(100%) 210(12%)

EXAMPLE 2.0 Production of 5-Bromo-2-chloro-4-(4,4,4-trifluorobutoxy)pyrimidine

3.19 g (14 mmol) of 5-bromo-2,4-dichloropyrimidine is mixed with 8.06 g (63 mmol) of 4,4,4-trifluorobutanol, and 0.74 ml (8.4 mmol) of trifluoromethanesulfonic acid is slowly added to it. The reaction mixture is stirred overnight at room temperature and then poured into water. The mixture is extracted by means of ethyl acetate, the combined organic phases are dried on MgSO₂, and the solvent is evaporated by means of underpressure. The product is always contaminated with varying amounts of 2,4-bisalkoxypyrimidine. The remaining material is therefore purified by means of gradient chromatography with silica gel as a carrier medium (eluant: hexane and hexane/ethyl acetate at a 9:1 ratio). This process results in a yield of 1.70 g (38%) and also yields 1.93 g (34%) of 5-bromo-2,4-bis-(4,4,4-trifluorobutoxy)pyrimidine (starting compound).

5-H 8.74(s, 1H) Chromatography: H to H/EA 9:1 4C 4.48(t, 2H) Yield: 38% H 2.00(mc, 2H) Melting point: 66.5-67.5° 2.44(mc, 2H) 5C H−

Similarly produced are also the following compounds:

Beispiel- 2.1 2.2 Nr. CDCl₃ DMSO 5-H 8.49(s, 1H) 8.75(s, 1H) 4CH 5.10(d, 2H) 4.05(mc, 2H) 3.79(mc, 2H) 3.60(mc, 2H) 5CH 2.59(t, 1H) 3.48(mc, 2H) 3.40(t, 2H) 1.07(t, 3H) Chrom. H to DCM to DCM/ H/EA 4:1 MeOH 95:5 Ausbeute 78% 11% Schmp. 55° C. Öl

Analogously to process examples 1 and 2, the following intermediate products are also produced:

Beispiel- 1-2.1 1-2.2 1-2.3 1-2.4 Nr. Löse- DMSO DMSO DMSO DMSO Mittel 8.26(s, 1H) 8.26(s, 1H) 8.29(s, 1H) 8.28(s, 1H) 6.65(d, 1H) 6.65(d, 1H) 6.32(s, 1H) 7.09(d, 1H) 4.70(t, 1H) 4.70(t, 1H) 4.89(t, 3H) 5.05(d, 1H) 4.10(dt, 1H) 4.10(dt, 1H) 3.74(d, 6H) 3.95(m, 1H) 3.65(at, 2H) 3.65(at, 2H) 3.60(m, 5H) 0.90(s, 9H) 0.90(s, 9H) 1.30(s, 3H) 1.28(s, 3H) Aus- 49% 70% 16% 92% beute Masse 309(EI) 309(EI) 314(EI) 354(EI)

Beispiel- 1-2.5 1-2.6 1-2.7 1-2.8 Nr. Löse- DMSO DMSO DMSO DMSO mittel 8.15(s, 1H) 8.22(s, 1H) 8.28(s, 1H) 8.22(s, 1H) 7.25(t, 1H) 4.82(t, 1H) 6.29(s, 1H) 7.23(d, 1H) 3.16(s, 2H) 4.49(br, 1H) 5.31(t, 1H) 4.60(d, 1H) 1.90(s, 3H) 3.85(m, 1H) 3.39(d, 2H) 3.85(m, 1H) 1.61(q, 6H) 3.76(m, 1H) 1.39(s, 6H) 3.35(m, 1H) 1.41(s, 6H) 3.54(m, 1H) 1.80(m, 4H) 3.40(m, 1H) 1.53(m, 2H) 1.93(m, 3H) 1.20(m, 2H) 1.80(m, 1H) Aus- 70% 75% 46% 24% beute Masse 357(EI) 293(EI) 281(EI) 305(EI)

Beispiel- 1-2.9 1-2.10 1-2.11 1-2.12 Nr. Löse- DMSO DMSO DMSO DMSO mittel 8.38(s, 1H) 8.22(s, 1H) 8.21(s, 1H) 8.31(s, 1H) 4.81(br, 1H) 7.05(d, 1H) 7.06(d, 1H) 7.32(d, 1H) 3.96(m, 2H) 4.82(t, 1H) 4.81(t, 1H) 4.35(s, 1H) 3.72(m, 1H) 4.18(m, 1H) 4.22(m, 1H) 3.68(s, 3H) 3.30(m, 2H) 3.42(m, 2H) 3.47(m, 2H) 2.32(m, 1H) 1.81(m, 2H) 1.15(d, 3H) 1.51(m, 2H) 0.90(dd, 6H) 1.48(m, 2H) 1.37(m, 1H) 0.88(m, 6H) Aus- 19% 71% 99% 77% beute Masse 292(EI) 266(EI) 308(EI) 322(ES)

Beispiel- 1-2.13 1-2.14 1-2.15 1-2.16 Nr. Löse- DMSO DMSO DMSO DMSO mittel 8.41(s, 1H) 8.25(s, 1H) 8.19(s, 1H) 8.19(s, 1H) 8.11(s, 1H) 4.53(m, 1H) 7.65(t, 1H) 7.30(d, 1H) 4.28(t, 2H) 3.88(m, 2H) 3.18(t, 2H) 3.65(m, 1H) 3.70(dd, 1H) 1.62(m, 6H) 1.68(m, 5H) 3.62(dd, 1H) 1.16(m, 3H) 1.25(m, 4H) 2.16(m, 1H) 0.90(m, 2H) 0.78(d, 3H) 2.02(m, 1H) 7.56(d, 1H) Aus- 46% 72% 68% 31% beute Masse 390(FAB) 277(EI) 303(EI) 305(EI)

Beispiel- 1-2.17 1-2.18 1-2.19 1-2.20 Nr. Löse- DMSO DMSO DMSO DMSO mittel 8.21(s, 1H) 8.35(t, 1H) 8.21(s, 1H) 8.20(s, 1H) 7.22(d, 1H) 8.19(s, 1H) 7.81(t, 1H) 7.71(t, 1H) 3.88(m, 1H) 3.40(m, 2H) 3.41(dd, 2H) 4.45(br, 1H) 1.70(m, 4H) 2.97(p, 1H) 2.31(m, 10H) 3.40(m, 4H) 1.50(m, 2H) 2.22(m, 4H) 2.13(s, 3H) 1.60(m, 2H) 1.28(m, 1H) 2.08(dd, 1H) 1.70(p, 2H) 1.44(m, 2H) 1.01(m, 2H) 1.70(m, 6H) 0.82(d, 3H) Aus- 22% 32% 28% 98% beute Masse 303(EI) 320(EI) 349(EI) 281(EI)

Beispiel- 1-2.21 1-2.22 1-2.23 1-2.24 Nr. Löse- DMSO DMSO DMSO DMSO mittel 8.25(s, 1H) 8.25(s, 1H) 8.20(s, 1H) 8.21(s, 1H) 8.08(d, 1H) 7.38(d, 1H) 7.28(d, 1H) 7.24(d, 1H) 7.35(m, 5H) 4.44(m, 1H) 4.19(m, 1H) 7.02(t, 1H) 5.30(m, 1H) 2.60(m, 2H) 2.40(m, 6H) 4.40(m, 1H) 4.81(t, 1H) 2.24(m, 2H) 1.50(m, 4H) 3.92(m, 1H) 3.45(m, 2H) 2.07(m, 2H) 1.15(d, 3H) 2.95(q, 2H) 2.05(m, 2H) 1.90(m, 2H) 0.91(t, 6H) 1.95(m, 2H) 1.82(m, 2H) 1.59(m, 2H) 1.3(m, 6H) 0.82(t, 3H) Aus- 97% 58% 52% 70% beute Masse 343(EI) 304(ES) 348(EI)

Diastereomer1/2

Diastereomer 1

Diastereomer 2

Diastereomer 1 Beispiel- 1-2.25 1-2.26 1-2.27 1-2.28 Nr. Löse- DMSO DMSO DMSO DMSO mittel 8.22(s, 1H) 8.25(s, 1H) 8.22(s, 1H) 7.21(d, 1H) 6.87(d, 1H) 7.28(d, 1H) 3.82(m, 1H) 4.02(m, 1H) 3.85(m, 1H) 2.45(m, 4H) 2.45(m, 4H) 2.19(s, 6H) 2.22(m, 1H) 2.22(m, 1H) 2.15(m, 1H) 1.78(m, 8H) 1.78(m, 8H) 1.82(m, 4H) 1.45(m, 6H) 1.45(m, 6H) 1.50(m, 2H) 1.25(m, 2H) Aus- n.b. 26% 23% 51% beute Masse 344(EI) 374(EI) 374(EI) 334(EI)

Diastereomer1 + 2(ca. 1:1)

Diastereomer1 + 2(ca. 1:1)

Diastereomer3 + 4(ca. 1:1)

Beispiel- 1-2.29 1-2.30 1-2.31 1-2.32 Nr. Löse- DMSO DMSO DMSO DMSO mittel 8.22(s, 2H) 8.21(s, 1H) 8.21(s, 1H) 8.71(s, 1H) 7.28(d, 1H) 7.18(d, 1H) 7.22(d, 1H) 5.32(m, 1H) 7.10(d, 1H) 4.62(s, 1H) 4.65(s, 1H) 3.82(m, 2H) 4.00(m, 1H) 4.20(m, 1H) 4.15(m, 1H) 3.55(m, 2H) 3.85(m, 1H) 3.95(m, 1H) 3.85(m, 1H) 2.00(m, 2H) 2.19(s, 6H) 2.75(dd, 1H) 2.78(m, 1H) 1.70(m, 2H) 2.17(s, 6H) 2.50(m, 2H) 2.60(m, 1H) 2.15(m, 1H) 2.31(dd, 1H) 2.38(dd, 1H) 2.00(m, 1H) 2.15(s, 1H) 1.95(m, 3H) 1.82(m, 8H) 2.00(m, 1H) 1.80(m, 2H) 1.50(m, 6H) 1.82(m, 4H) 1.52(m, 3H) 1.25(m, 2H) 1.55(m, 5H) 1.20(m, 2H) Aus- 13% 35% 21% 40% beute Masse 334(EI) 374(EI) 374(EI) 292(EI)

Beispiel- 1-2.33 1-2.34 Nr. Löse- DMSO CDCl3 mittel 8.50(s, 1H) 8.08(s, 1H) 4.10(m, 2H) 6.04(m, 1H) 3.72(m, 1H) 5.71(br, 1H) 3.30(m, 2H) 4.48(d, 2H) 1.75(m, 2H) 3.71(s, 3H) 1.35(m, 2H) 2.25(s, 3H) Aus- 3% 30% beute Masse 291(EI) 300(ES)

Diastereomer1 + 2(ca. 1:1) Beispiel- 1-2.35 1-2.36 Nr. Löse- DMSO CDCl3 mittel 8.23(s, 1H) 8.11(s, 2H, 1 + 2) 7.27(d, 1H) 5.55(m, 1H, 1) 7.04(t, 1H) 5.29(m, 1H, 2) 4.46(m, 1H) 4.25(m, 1H, 1) 3.95(m, 1H) 3.98(m, 1H, 2) 2.94(m, 2H) 3.72(m, 8H, 1 + 2) 1.92(m, 4H) 2.65(m, 8H, 1 + 2) 1.62(m, 2H) 1.70 1.32(m, 6H) (m, 18H, 1 + 2) 0.84(t, 3H) Aus- 70% 66% beute Masse 405(ES) 375(ES)

Beispiel- 1-2.37 1-2.38 1-2.39 1-2.40 Nr. Löse- CDCl3 CDCl3 DMSO DMSO mittel 8.14(s, 1H) 8.20(s, 1H) 8.22(s, 1H) 8.22(s, 1H) 5.41(m, 1H) 7.71(m, 1H) 6.35(s, 1H) 7.12(d, 1H) 4.49(m, 1H) 7.30(m, 6H) 5.19(t, 1H) 4.10(m, 1H) 2.44(m, 6H) 4.97(s, 2H) 3.54(d, 2H) 2.20(m, 1H) 1.79(m, 2H) 3.00(m, 2H) 2.00(m, 2H) 1.89(m, 1H) 1.40(m, 8H) 1.75(m, 4H) 1.35(m, 8H) 1.53(m, 2H) Aus- 58% 77% 48% 60% beute Masse 304(ES) 427(ES) 308(EI) 301(EI)

Beispiel- 1-2.41 1-2.42 1-2.43 1-2.44 Nr. Löse- DMSO DMSO DMSO DMSO mittel 8.19(s, 1H) 8.21(s, 1H) 8.28(s, 1H) 8.41(s, 1H) 7.21(d, 1H) 7.03(d, 1H) 3.62(q, 4H) 8.15(t, 1H) 4.03(m, 1H) 4.83(t, 1H) 1.18(t, 6H) 4.21(td, 12H) 1.60(m, 12H) 4.13(m, 1H) 3.47(m, 2H) 1.12(d, 3H) Aus- 73% 61% 13% 21% beute Masse 303(EI) 267(EI) 265(EI) 339(EI)

Beispiel- 1-2.45 1-2.46 1-2.47 1-2.48 Nr. Löse- DMSO DMSO DMSO DMSO mittel 8.36(s, 1H) 8.26(s, 1H) 8.32(t, 1H) 8.15(s, 1H) 6.56(s, 1H) 8.06(d, 1H) 8.15(s, 1H) 7.06(d, 1H) 3.81(s, 1H) 7.30(m, 5H) 3.40(m, 2H) 4.65(br, 1H) 2.28(m, 2H) 5.29(m, 1H) 2.34(m, 2H) 3.79(m, 1H) 1.83(m, 2H) 4.81(t, 1H) 2.18(s, 6H) 3.52(m, 1H) 1.58(m, 6H) 3.42(m, 2H) 1.69(m, 2H) 1.86(m, 2H) 2.10(m, 2H) 1.61(m, 2H) 1.25(m, 4H) Aus- 84% 97% 22% 53% beute Masse 314(EI) 343(EI) 294(EI) 307(EI)

Beispiel- 1-2.49 1-2.50 1-2.51 1-2.52 Nr. Löse- DMSO DMSO DMSO mittel 8.29(s, 1H) 8.18(s, 1H) 8.29(s, 1H) 8.38(s, 1H) 6.05(s, 1H) 7.25(d, 1H) 6.18(s, 1H) 7.28(d, 1H) 5.18(m, 1H) 4.15(m, 1H) 5.15(t, 1H) 5.28(t, 1H) 3.54(s, 2H) 2.40(m, 6H) 3.70(m, 1H) 4.65(m, 1H) 1.92(m, 2H) 1.50(m, 4H) 3.49(m, 1H) 3.86(m, 2H) 1.70(m, 2H) 1.17(d, 3H) 2.60(m, 1H) 3.65(s,3H) 0.90(dd, 6H) 0.92(d, 3H) 0.83(d, 3H) Aus- 16% 52% 27% 63% beute Masse 308(EI) 350(EI) 308(EI) 309(EI)

Beispiel- 1-2.53 1-2.54 1-2.55 Nr. Löse- DMSO DMSO DMSO mittel 8.22(s, 1H) 7.75(s, 1H) 8.18(s, 1H) 7.65(t, 1H) 6.55(d, 1H) 7.69(t, 1H) 7.30(m, 6H) 4.54(m, 1 4.32(br, 1H) 5.01(s, 2H) 3.35(m, 4H) 3.38(m, 2H) 1.40(m, 6H) 3.04(m, 2H) 1.68(m, 2H) Aus- 77% 50% 43% beute Masse 398(EI) 229(EI) 295(EI)

EXAMPLE 3.0 Production of Amines

4.5 g (20 mmol) of 2-bromobutyraldehyde diethyl acetyl (Pfaltz-Bauer Company) and 5.2 g (80 mmol) of sodium azide are stirred for 5 days in 15 ml of DMF at 100° C. Then, it is poured onto cold dilute sodium bicarbonate solution, extracted 3× with ether, the organic phase is dried with magnesium sulfate and concentrated by evaporation: raw yield 1.87 g (50% of theory).

936 mg of the crude product is dissolved in 50 ml of methanol, mixed with palladium on carbon (10%) and stirred for 12 hours under H₂ atmosphere. After the catalyst is filtered off and after concentration by evaporation, 457 mg (57% of theory) of the desired amine remains.

Beispiel- 3.0 3.1 3.2 3.3 Nr. Ausbeute 50% 57% 50% 71% NMR 4.38(d, 1H) 4.19(d, 1H) 4.38(d, 1H) 4.25(d, 1H) CDCl3 3.72(m, 2H) 3.68(m, 2H) 3.58(m, 2H) 3.5(m, 1H) 3.6(m, 2H) 3.52(m, 2H) 3.5(m, 1H) 3.42(s, 3H) 3.25(m 1H) 2.7(m, 1H) 3.49(s, 3H) 3.41(s, 3H) 1.7(m, 1H) 1.60(m, 1H) 3.43(s, 3H) 3.40(m, 1H) 1.46(m, 1H) 1.25(m, 1H) 3.39(s, 3H) 3.08(m, 1H) 1.25(trtr, 6H) 1.2(trtr, 6H) 1.0(tr, 3H) 0.95(tr, 3H)

EXAMPLE 4.0 Production of the Free Aldehydes

148 mg (0.5 mmol) of intermediate product compound 1.18 is dissolved in 1 ml of glacial acetic acid. At room temperature, 0.5 ml of 1N hydrochloric acid is added, and it is stirred for 12 hours. For working-up, it is poured onto ice water and carefully neutralized with pulverized sodium bicarbonate. Then, it is extracted 3× with ethyl acetate, the organic phase is dried with magnesium sulfate and concentrated by evaporation, crude product 104 mg (83% of theory) of the aldehyde of compound 4.0. The crude product can be used without further purification.

Beispiel- 4.1 4.0 4.2 4.3 Nr. Aus- 82% 83% 89% 79% beute Masse ESI: ESI: ESI: ESI: MH⁺ 278(39%) MH⁺ 250(9%) MH⁺ 266(8%) MH+ 294(10%) 210(100%)

EXAMPLE 5.0 Production of Ketones

100 mg (0.356 mmol) of compound 6.0 and 126 mg of N-methylmorpholine-N-oxide are dissolved in 5 ml of dichloromethane and stirred for 10 minutes with pulverized molecular sieve (4 A). Then, 6 mg of tetrapropylammonium perruthenate is added, and it is stirred for 4 more hours at room temperature. After concentration by evaporation, it is chromatographed on silica gel (hexane/ethyl acetate 4:1>2:1). Yield: 75 mg (76% of theory) of the ketone of compound 5.0.

Beispiel- 5.0 Nr. Aus- 76% beute Masse ESI: MH⁺ 280(100%) 200(37%) 156(30%)

EXAMPLE 6.0 Production of Alcohols

265 mg (1 mmol) of compound 4.2 is dissolved in 20 ml of tetrahydrofuran. While being cooled in an ice bath, 5 equivalents of methylmagnesium bromide (3 molar solution in ether) is added in portions. Then, it is stirred for 3 more hours at room temperature and then quenched with water while being cooled. Then, it is mixed with ammonium chloride solution, extracted 3× with ethyl acetate, the organic phase is dried with magnesium sulfate and concentrated by evaporation. Flash chromatography (hexane/ethyl acetate 2:1) yields 213 mg (76% of theory) of the alcohol of compound 6.0.

ESI:MH⁺ 282 (100%) 276 (5%)

Similarly produced are also the following intermediate products:

Beispiel- 6.1 6.2 6.3 Nr. Aus- 46% 32% 39% beute Masse EI: ESI: ESI: M⁺ 267(3%) MH⁺ 308(100%) MH⁺ 296(100%) 223(100%) 306(71%) 294(73%) 132(27%) 268(31%) 217(4%)

Beispiel- 6.4 6.5 Nr. Aus- 36% 50% beute Masse EI: ESI: M+ 281(3%) MH⁺ 310(100%) 223(100%) 308(87%) 114(38%) 298(9%)

Beispiel- 6.6 6.7 6.8 Nr. Aus- 40% ~20% 35% beute Masse EI: Cl: ESI: M⁺ 358(100%) M⁺ 310(100%) MH⁺ 294(28%) 356(97%) 308(84%) 296(36%) 277(29%) 130(54%) 210(100%)

Beispiel- 6.9 6.10 Nr. Aus- 29% 67% beute Masse ESI: ESI: MH⁺ 308(28%) MH+ 310(87%) 310(38%) 312(100%) 210(100%) 123(24%)

Subjects of this invention are thus also compounds of general formula Ia

in which

D stands for halogen, and X, R¹, and R² have the meanings that are indicated in general formula (I).

Those intermediate products of general formula Ia, in which D stands for chlorine and X, R¹ and R² have the meanings that are indicated in the general formula, are especially valuable.

Another subject of this invention are also those compounds that fall under industrial property right DE 4029650, whose action is in the fungicide range and which are not described as CDK inhibitors, however, and also their use for treating cancer is not described.

No. Structure Name 5

4-[[5-Bromo-4-(2-propynylamino)-2-pyrimidinyl]amino]-phenol 6

4-[[5-Bromo-4-(2-propynyloxy)-2-pyrimidinyl]amino]-phenol 16

5-Bromo-N2-(4-methylthiophenyl)-N4-2-propynyl-2,4-pyrimidine diamine 22

1-[4-[(5-Bromo-4-(2-propynyloxy)-2-pyrimidinyl)amino]phenyl]-ethanone 23

5-Bromo-N2-(4-difluoromethylthiophenyl)-N4-2-propynyl-2,4-pyrimidine diamine 24

5-Bromo-N4-2-propynyl-N2-(4-trifluoromethylthiophenyl)-2,4-pyrimidine diamine 35

5-Bromo-N4-2-propynyl-N2-(3-trifluoromethylthiophenyl)-2,4-pyrimidine diamine 37

N-[5-Bromo-4-(2-propynylamino)-2-pyrimidinyl]-indazol-5-amine 38

N-[5-Bromo-4-(2-propynylamino)-2-pyrimidinyl]-benzothiazole-5-amine 42

4-[[5-Fluoro-4-(2-propynyloxy)-2-pyrimidinyl]amino]-phenol 43

4-[[5-Chloro-4-(2-propynyloxy)-2-pyrimidinyl]amino]-phenol 50

1-[4-[(5-Bromo-4-(2-propynylamino)-2-pyrimidinyl)amino]phenyl]-ethanone 54

1-[4-[(5-Iodo-4-(2-propynylamino)-2-pyrimidinyl)amino]phenyl]-ethanone 70

1-[4-[(5-Ethyl-4-(2-propynylamino)-2-pyrimidinyl)amino]phenyl]-ethanone 81

1-[4-[(5-Bromo-4-(2-propynylamino)-2-pyrimidinyl)amino]phenyl]-ethanol 82

1-[4-[(5-Bromo-4-(2-propynyloxy)-2-pyrimidinyl)amino]phenyl]-ethanol

The invention thus relates in addition to pharmaceutical agents that comprise a compound of general formula I in which

-   -   R¹ stands for halogen or C₁-C₃-alkyl     -   X stands for oxygen or —NH,     -   A stands for hydrogen     -   B stands for hydroxy, —CO-alkyl-R⁷, —S—CHF₂,         —S—(CH₂)_(n)CH(OH)CH₂N—R³R⁴, —S—CF₃, or —CH—(OH)—CH₃, or     -   A and B, independently of one another, can form a group

R², R³, R⁴, R⁷ and R⁸ have the meanings that are indicated in general formula I, as well as isomers, diastereomers, enantiomers and salts thereof.

The agents according to the invention can also be used for treating cancer, auto-immune diseases, cardiovascular diseases, chemotherapy agent-induced alopecia and mucositis, infectious diseases, nephrological diseases, chronic and acute neurodegenerative diseases and viral infections, whereby cancer is defined as solid tumors and leukemia; auto-immune diseases are defined as psoriasis, alopecia and multiple sclerosis; cardiovascular diseases are defined as stenoses, arterioscleroses and restenoses; infectious diseases are defined as diseases that are caused by unicellular parasites; nephrological diseases are defined as glomerulonephritis; chronic neurodegenerative diseases are defined as Huntington's disease, amyotrophic lateral sclerosis, Parkinson's disease, AIDS dementia and Alzheimer's disease; acute neurodegenerative diseases are defined as ischemias of the brain and neurotraumas; and viral infections are defined as cytomegalic infections, herpes, hepatitis B or C, and HIV diseases.

The following examples describe the biological action of the compounds according to the invention without limiting the invention to these examples.

EXAMPLE 1 CDK2/CycE Kinase Assay

Recombinant CDK2- and CycE-GST-fusion proteins, purified from baculovirus-infected insect cells (Sf9), were obtained by Dr. Dieter Marmé, Klinik für Tumorbiologie [Clinic for Tumor Biology], Freiburg. Histone IIIS, which was used as a kinase substrate, was purchased by the Sigma Company.

CDK2/CycE (50 ng/measuring point) was incubated for 15 minutes at 22° C. in the presence of various concentrations of test substances (0 μm, as well as within the range of 0.01-100 μm) in assay buffer [50 mmol of tris/HCl pH 8.0, 10 mmol of MgCl₂, 0.1 mmol of Na ortho-vanadate, 1.0 mmol of dithiothreitol, 0.5 μm. of adenosine triphosphate (ATP), 10 μg/measuring point of histone IIIS, 0.2 μCi/measuring point of ³³P-gamma ATP, 0.05% NP40, 12.5% dimethyl sulfoxide]. The reaction was stopped by adding EDTA solution (250 mmol, pH 8.0, 14 μl/measuring point).

From each reaction batch, 10 μl was applied to P30 filter strips (Wallac Company), and non-incorporated ³³P-ATP was removed by subjecting the filter strips to three washing cycles for 10 minutes each in 0.5% phosphoric acid. After the filter strips were dried for one hour at 70° C., the filter strips were covered with scintillator strips (MeltiLex™ A, Wallac Company) and baked for one hour at 90° C. The amount of incorporated ³³P (substrate phosphorylation) was determined by scintillation measurement in a gamma-radiation measuring device (Wallac).

EXAMPLE 2 Proliferation Assay

Cultivated human tumor cells (as indicated) were flattened out at a density of 5000 cells/measuring point in a 96-hole multititer plate in 200 μl of the corresponding growth medium. After 24 hours, the cells of one plate (zero-point plate) were colored with crystal violet (see below), while the medium of the other plates was replaced by fresh culture medium (200 μl), to which the test substances were added at various concentrations (0 μm, as well as in the range of 0.01-30 μm; the final concentration of the solvent dimethyl sulfoxide was 0.5%). The cells were incubated for 4 days in the presence of test substances. The cell proliferation was determined by coloring the cells with crystal violet: the cells were fixed by adding 20 μl/measuring point of a 11% glutaric aldehyde solution for 15 minutes at room temperature. After three washing cycles of the fixed cells with water, the plates were dried at room temperature. The cells were colored by adding 100 μl/measuring point of a 0.1% crystal violet solution (pH was set at 3 by adding acetic acid). After three washing cycles of the colored cells with water, the plates were dried at room temperature. The dye was dissolved by adding 100 μl/measuring point of a 10% acetic acid solution. The extinction was determined by photometry at a wavelength of 595 nm. The change of cell growth, in percent, was calculated by standardization of the measured values to the extinction values of the zero-point plate (=0%) and the extinction of the untreated (0 μm) cells (=100%).

The results of Examples 1 and 2 are cited in the following tables.

[Key to Subsequent Tables:]

-   Beispiel Nummer=Example Number

Inhibition Beispiel IC₅₀ [nM] Proliferation IC₅₀ [μM] Sw Nummer CDK2/CycE MCF7 H460 HCT116 DU145 (g/l) 22 40 1.2 1.5 1.5 1.5 0.003 37 70 4 0.006 6 70 4 6 0.008 40 20 1 3 3 9 0.002 51 70 8 20 60 4 21 400 2 1 300 8 2 700 16 300 3 24 400 5 26 300 3 35 120 >10 23 180 3 11 6 0.2 0.5 0.3 0.2 38 80 >10 34 1800 10 4 0.2 0.5 0.5 0.5 12 400 4 25 70 1.2 1.5 1.1 1.2 0.017 9 7 0.9 3 3 7 6 0.7 1.5 1.2 0.5 0.028 31 800 7 0.0023 14 200 3 0.013 18 2000 0.039 3 200 8 0.039 19 800 >10 0.041 13 2000 >10

Inhibition Beispiel IC₅₀ [nM] Proliferation IC₅₀ [μM] Sw Nummer CDK2/CycE MCF7 H460 HCT116 DU145 (g/l) 17 1000 >10 0.04 4 40 8 0.042 15 300 >10 0.024 8 <10 4 0.007 43 200 6 0.04 36 30 0.4 0.6 0.5 0.6 0.018 27 >10000 42 2000 0.043 39 300 0.0016 44 8 1.2 0.4 0.4 0.3 0.005 45 10 2 1.7 1.2 0.5 0.0094 50 150 5 90 10 0.043 46 7 2 0.0069 52 200 0.2 1.6 1.2 2 0.0005 53 300 1.6 0.026 54 100 1.1 0.0015 47 12 0.7 1.8 1.3 0.9 56 80 4 0.023 49 50 >10 0.044 48 4 0.2 1 0.4 0.3 0.042 96 400 0.0005 98 2000 85 2000 0.001 84 400 0.0005 86 3000 87 250 0.8 0.003 22 40 1.2 1.5 1.5 1.5 0.003

Inhibition Beispiel IC₅₀ [nM] Proliferation IC₅₀ [μM] Sw Nummer CDK2/CycE MCF7 H460 HCT116 DU145 (g/l) 37 70 4 0.006 6 70 4 6 0.008 16 300 3 24 400 5 35 120 >10 23 180 3 38 80 >10 43 200 6 0.04 42 2000 0.043 50 150 5 90 10 0.043 54 100 1.1 0.0015

Proof of Superiority of the Compounds According to the Invention Compared to the Known Compounds

To prove the superiority of the compounds according to the invention compared to the known compounds, the compounds according to the invention were compared to known reference compounds and structurally-similar known compounds in the enzyme test. The result is cited in the following table:

[Key to the Following Tables:]

-   Beispiel-Nr.=Example No. -   Löslichkeit (g/l)=Solubility (g/l) -   Beispiel 11 aus WO01/14375 (Seite 38)=Example 11 from WO01/14375     (page 38)

CDK2/ Loslich- CycE MCF-7 keit Beispiel-Nr. R² A IC₅₀ [nM] IC₅₀ [μM] (g/l)

Nr. 48 CH(C₃H₇)—CH₂—OH— —SO₂—N—(CH₂)₂—OH 4 0.2 0,042

Nr. 9 CH(CH₂OH)₂ SO₂NH₂ 7 0.9 0,009

Nr. 11 Propargyl-NH— SO₂NH₂ 6 0.2

CDK2/ Löslich- CycE MCF-7 keit Beispiel-Nr. R² A IC₅₀ [nM] IC₅₀ [μM] (g/l)

Olomoucine 7000 30

Roscovitine 1500 8

Kenpaullone 1800 6

Alsterpaullone 90 1.2

Purvalanol A 10 2

CDK2/ Löslich- CycE MCF-7 keit Beispiel-Nr. R² A IC₅₀ [nM] IC₅₀ [μM] (g/l) Beispiel 11 ausWO01/14375(Seite 38)

190

It can be seen from the results of the table that both in the enzyme test and in the cell test, the compounds according to the invention have significantly higher activities in the enzyme and in the MCF-7 cells than the compounds that are known from the prior art. The compounds according to the invention are thus far superior to the known compounds. 

1. Compounds of general formula I

in which R¹ stands for hydrogen, halogen, C₁-C₆-alkyl, nitro, or for the group —COR⁵, —OCF₃, —(CH₂)_(n)R⁵, —S—CF₃ or —SO₂CF₃, R² stands for C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkinyl, or C₃-C₁₀-cycloalkyl or for C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkinyl, or C₃-C₁₀-cycloalkyl that is substituted in one or more places in the same way or differently with hydroxy, halogen, C₁-C₆-alkoxy, C₁-C₆-alkylthio, amino, cyano, C₁-C₆-alkyl, —NH—(CH₂)_(n)—C₃-C₁₀-cycloalkyl, C₃-C₁₀-cycloalkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, C₂-C₆-alkinyl, C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkoxy-C₁-C₆-alkyl, —NHC₁-C₆-alkyl, —N(C₁-C₆-yl)₂, —SO(C₁-C₆-alkyl), —SO₂(C₁-C₆-alkyl), C₁-C₆-alkanoyl, —CONR³R⁴, —COR⁵, C₁-C₆-alkylOAc, carboxy, aryl, heteroaryl, —(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl, phenyl-(CH₂)_(n)—R⁵, —(CH₂)_(n)PO₃(R⁵)₂ or with the group —R⁶ or —NR³R⁴, and the phenyl, C₃-C₁₀-cycloalkyl, aryl, heteroaryl, —(CH₂)_(n)-aryl and —(CH₂)_(n)-heteroaryl itself optionally can be substituted in one or more places in the same way or differently with halogen, hydroxy, C₁-C₆-alkyl, C₁-C₆-alkoxy, heteroaryl, benzoxy or with the group —CF₃ or —OCF₃, and the ring of the C₃-C₁₀-cycloalkyl and the C₁-C₁₀-alkyl optionally can be interrupted by one or more nitrogen, oxygen and/or sulfur atoms and/or can be interrupted by one or more ═C═O groups in the ring and/or optionally one or more possible double bonds can be contained in the ring, or R² stands for the group

X stands for oxygen or for the group —NH—, —N(C₁-C₃-alkyl) or for —OC₃-C₁₀-cycloalkyl, which can be substituted in one or more places in the same way or differently with a heteroaromatic compound, or X and R² together form a C₃-C₁₀-cycloalkyl ring, which optionally can contain one or more heteroatoms and optionally can be substituted in one or more places with hydroxy, C₁-C₆-alkyl, C₁-C₆-alkoxy or halogen, A and B, in each case independently of one another, stand for hydrogen, hydroxy, C₁-C₃-alkyl, C₁-C₆-alkoxy or for the group —SR⁷, —S(O)R⁷, —SO₂R⁷, —NHSO₂R⁷, —CH(OH)R⁷, —CR⁷(OH)—R⁷, C₁-C₆-alkylP(O)OR³OR⁴ or —COR⁷, or for

or A and B together form a C₃-C₁₀-cycloalkyl ring that optionally can be interrupted by one or more nitrogen, oxygen and/or sulfur atoms and/or can be interrupted by one or more ═C═O or ═SO₂ groups in the ring and/or optionally one or more possible double bonds can be contained in the ring, and the C₃-C₁₀-cycloalkyl ring optionally can be substituted in one or more places in the same way or differently with hydroxy, halogen, C₁-C₆-alkoxy, C₁-C₆-alkylthio, amino, cyano, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₃-C₁₀-cycloalkyl, C₁-C₆-alkoxy-C₁-C₆-alkyl, —NHC₁-C₆-alkyl, —N(C₁-C₆-alkyl)₂, —SO(C₁-C₆-alkyl), —SO₂R⁷, C₁-C₆-alkanoyl, —CONR³R⁴, —COR⁵, C₁-C₆-alkoxyOAc, phenyl or with the group R⁶, whereby the phenyl itself optionally can be substituted in one or more places in the same way or differently with halogen, hydroxy, C₁-C₆-alkyl, C₁-C₆-alkoxy or with the group —CF₃ or —OCF₃, R³ and R⁴, in each case independently of one another, stand for hydrogen, phenyl, benzyloxy, C₁-C₁₂-alkyl, C₁-C₆-alkoxy, C₂-C₄-alkenyloxy, C₃-C₆-cycloalkyl, hydroxy, hydroxy-C₁-C₆-alkyl, dihydroxy-C₁-C₆-alkyl, heteroaryl, heterocyclo-C₃-C₁₀-alkyl, heteroaryl-C₁-C₃-alkyl, C₃-C₆-cycloalkyl-C₁-C₃-alkyl that is optionally substituted with cyano, or for C₁-C₆-alkyl that is optionally substituted in one or more places in the same way or differently with phenyl, pyridyl, phenyloxy, C₃-C₆-cycloalkyl, C₁-C₆-alkyl or C₁-C₆-alkoxy, whereby the phenyl itself can be substituted in one or more places in the same way or differently with halogen, C₁-C₆-alkyl, C₁-C₆-alkoxy or with the group —SO₂NR³R⁴, or for the group —(CH₂)_(n)NR³R⁴, —CNHNH₂ or —NR³R⁴, or R³ and R⁴ together form a C₃-C₁₀-cycloalkyl ring that optionally can be interrupted by one or more nitrogen, oxygen and/or sulfur atoms and/or can be interrupted by one or more ═C═O groups in the ring and/or optionally one or more possible double bonds can be contained in the ring, R⁵ stands for hydroxy, phenyl, C₁-C₆-alkyl, C₃-C₆-cycloalkyl, benzoxy, C₁-C₆-alkylthio or C₁-C₆-alkoxy, R⁶ stands for a heteroaryl or C₃-C₁₀-cycloalkyl ring, whereby the ring has the above-indicated meaning, R⁷ stands for halogen, hydroxy, phenyl, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkinyl, C₃-C₁₀-cycloalkyl, with the above-indicated meaning, or for the group —NR³R⁴, or for a C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkinyl or C₃-C₇-cycloalkyl that is substituted in one or more places in the same way or differently with hydroxy, C₁-C₆-alkoxy, halogen, phenyl, —NR³R⁴ or phenyl, which itself can be substituted in one or more places in the same way or differently with halogen, hydroxy, C₁-C₆-alkyl, C₁-C₆-alkoxy, halo-C₁-C₆-alkyl, halo-C₁-C₆-alkoxy, or R⁷ stands for-phenyl, which itself can be substituted in one or more places in the same way or differently with halogen, hydroxy, C₁-C₆-alkyl or C₁-C₆-alkoxy, halo-C₁-C₆-alkyl, or halo-C₁-C₆-alkoxy, R⁸, R⁹ and R¹⁰, in each case independently of one another, stand for hydrogen, hydroxy, C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkinyl, C₃-C₁₀-cycloalkyl, aryl, heteroaryl or for C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkinyl or C₃-C₁₀-cycloalkyl that is optionally substituted in one or more places in the same way or differently with hydroxy, halogen, C₁-C₆-alkoxy, C₁-C₆-alkylthio, amino, cyano, C₁-C₆-alkyl, —NH—(CH₂)_(n)—C₃-C₁₀-cycloalkyl, C₃-C₁₀-cycloalkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, C₂-C₆-alkinyl, C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkoxy-C₁-C₆-alkyl, —NHC₁-C₆-alkyl, —N(C₁-C₆-alkyl)₂, —SO(C₁-C₆-alkyl), —SO₂(C₁-C₆-alkyl), C₁-C₆-alkanoyl, —CONR³R⁴, —COR⁵, C₁-C₆-alkylOAc, carboxy, aryl, heteroaryl, —(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl, phenyl-(CH₂)_(n)—R⁵, —(CH₂)_(n)PO₃(R⁵)₂ or with the group —R⁶ or —NR³R⁴, and the phenyl, C₃-C₁₀-cycloalkyl, aryl, heteroaryl, —(CH₂)_(n)-aryl and —(CH₂)_(n)-heteroaryl itself optionally can be substituted in one or more places in the same way or differently with halogen, hydroxy, C₁-C₆-alkyl, C₁-C₆-alkoxy or with the group —CF₃ or —OCF₃, and the ring of C₃-C₁₀-cycloalkyl and the C₁-C₁₀-alkyl optionally can be interrupted by one or more nitrogen, oxygen and/or sulfur atoms and/or can be interrupted by one or more ═C═O groups in the ring and/or optionally one or more possible double bonds can be contained in the ring, and n stands for 0-6, as well as isomers, diastereomers, enantiomers and salts thereof
 2. Compounds of general formula I, according to claim 1, in which R¹ stands for hydrogen, halogen, C₁-C₆-alkyl, nitro, or for the group —COR⁵, —OCF₃, —(CH₂)_(n)R⁵, —S—CF₃ or —SO₂CF₃, R² stands for C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkinyl, or C₃-C₁₀-cycloalkyl or for C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkinyl, or C₃-C₁₀-cycloalkyl that is substituted in one or more places in the same way or differently with hydroxy, halogen, C₁-C₆-alkoxy, C₁-C₆-alkylthio, amino, cyano, C₁-C₆-alkyl, —NH—(CH₂)_(n)—C₃-C₁₀-cycloalkyl, C₃-C₁₀-cycloalkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, C₂-C₆-alkinyl, C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkoxy-C₁-C₆-alkyl, —NHC₁-C₆-alkyl, —N(C₁-C₆-alkyl)₂, —SO(C₁-C₆-alkyl), —SO₂(C₁-C₆-alkyl), C₁-C₆-alkanoyl, —CONR³R⁴, —COR⁵, C₁-C₆-alkyOAc, carboxy, aryl, heteroaryl, —(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl, phenyl-(CH₂)_(n)—R⁵, —(CH₂)_(n)PO₃(R⁵)₂ or with the group —R⁶ or —NR³R⁴, and the phenyl, C₃-C₁₀-cycloalkyl, aryl, heteroaryl, —(CH₂)_(n)-aryl and —(CH₂)_(n)-heteroaryl itself optionally can be substituted in one or more places in the same way or differently with halogen, hydroxy, C₁-C₆-alkyl, C₁-C₆-alkoxy, heteroaryl, benzoxy or with the group —CF₃ or —OCF₃, and the ring of the C₃-C₁₀-cycloalkyl and the C₁-C₁₀-alkyl optionally can be interrupted by one or more nitrogen, oxygen and/or sulfur atoms and/or can be interrupted by one or more ═C═O groups in the ring and/or optionally one or more possible double bonds can be contained in the ring, or R² stands for the group

X stands for oxygen or for the group —NH—, —N(C₁-C₃-alkyl) or for —OC₃-C₁₀-cycloalkyl, which can be substituted in one or more places in the same way or differently with a heteroaromatic compound, or X and R² together form a C₃-C₁₀-cycloalkyl ring, which optionally can contain one or more heteroatoms and optionally can be substituted in one or more places with hydroxy, C₁-C₆-alkyl, C₁-C₆-alkoxy or halogen, A and B, in each case independently of one another, stand for hydrogen, hydroxy, C₁-C₃-alkyl, C₁-C₆-alkoxy or for the group —S—CH₃, —SO₂—C₂H₄—OH, —CO—CH₃, —S—CHF₂, —S—(CH₂)_(n)CH(OH)CH₂N—R³R⁴, —CH₂P(O)OR³OR⁴, —S—CF₃, —SO—CH₃, —SO₂CF₃, —SO₂—(CH₂)_(n)—N—R³R⁴, —SO₂—NR³R⁴, —SO₂R⁷, —CH—(OH)—CH₃ or for

or A and B together can form a group

R³ and R⁴, in each case independently of one another, stand for hydrogen, phenyl, benzyloxy, C₁-C₁₂-alkyl, C₁-C₆-alkoxy, C₂-C₄-alkenyloxy, C₃-C₆-cycloalkyl, hydroxy, hydroxy-C₁-C₆-alkyl, dihydroxy-C₁-C₆-alkyl, heteroaryl, heterocyclo-C₃-C₁₀-alkyl, heteroaryl-C₁-C₃-alkyl, C₃-C₆-cycloalkyl-C₁-C₃-alkyl optionally substituted with cyano, or for C₁-C₆-alkyl that is optionally substituted in one or more places in the same way or differently with phenyl, pyridyl, phenyloxy, C₃-C₆-cycloalkyl, C₁-C₆-alkyl or C₁-C₆-alkoxy, whereby the phenyl itself can be substituted in one or more places in the same way or differently with halogen, trifluoromethyl, C₁-C₆-alkyl, C₁-C₆-alkoxy or with the group —SO₂NR³R⁴, or for the group —(CH₂)_(n)NR³R⁴, —CNHNH₂ or —NR³R⁴ or for

or which optionally can be substituted with C₁-C₆-alkyl, R⁵ stands for hydroxy, phenyl, C₁-C₆-alkyl, C₃-C₆-cycloalkyl, benzoxy, C₁-C₆-alkylthio or C₁-C₆-alkoxy, R⁶ stands for the group

R⁷ stands for halogen, hydroxy, phenyl, C₁-C₆-alkyl, —C₂H₄OH, —NR³R⁴, or the group

R⁸, R⁹ and R¹⁰, in each case independently of one another, stand for hydrogen, hydroxy, C₁-C₆-alkyl, C₃-C₆-cycloalkyl or for the group

and n stands for 0-6, as well as isomers, enantiomers, diastereomers, and salts thereof.
 3. Compounds of general formula I, according to claims 1 and 2, in which R¹ stands for hydrogen, halogen, C₁-C₃-alkyl, or for the group —(CH₂)_(n)R⁵, R² stands for —CH(CH₃)—(CH₂)_(n)—R⁵, —CH—(CH₂OH)₂, —(CH₂)_(n)R⁷, —CH(C₃H₇)—(CH₂)_(n)—R5, —CH(C₂H₅)—(CH₂)_(n)—R⁵, —CH₂—CN, —CH(CH₃)COCH₃, —CH(CH₃)—C(OH)(CH₃)₂, —CH(CH(OH)CH₃)OCH₃, —CH(C₂H₅)CO—R⁵, C₂-C₄-alkinyl, —(CH₂)_(n)—COR⁵, —(CH₂)_(n)—CO—C₁-C₆-alkyl, —(CH₂)_(n)—C(OH)(CH₃)-phenyl, —CH(CH₃)—C(CH₃)—R⁵, —CH(CH₃)—C(CH₃)(C₂H₅)—R⁵, —CH(OCH₃)—CH₂—R⁵, —CH₂—CH(OH)—R⁵, —CH(OCH₃)—CHR⁵—CH₃, —CH(CH₃)—CH(OH)—CH₂—CH═CH₂, —CH(C₂H₅)—CH(OH)—(CH₂)_(n)—CH₃, —CH(CH₃)—CH(OH)—(CH₂)_(n)—CH₃, —CH(CH₃)—CH(OH)—CH(CH₃)₂, (CH₂OAC)₂, —(CH₂)_(n)—R⁶, —(CH₂)_(n)—(CF₂)_(n)—CF₃, —CH(CH₂)_(n)—R⁵)₂, —CH(CH₃)—CO—NH₂, —CH(CH₂OH)-phenyl, —CH(CH₂OH)—CH(OH)—(CH₂)_(n)R⁵, —CH(CH₂OH)—CH(OH)-phenyl, —CH(CH₂OH)—C₂H₄—R⁵, —(CH₂)_(n)—C≡C—C(CH₃)═CH—COR⁵, —CH(Ph)-(CH₂)_(n)—R⁵, —(CH₂)_(n)COR⁵, —(CH₂)_(n)PO₃(R⁵)₂, —(CH₂)_(n)—COR⁵, —CH((CH₂)_(n)OR⁵)CO—R⁵, —(CH₂)_(n)CONHCH((CH₂)_(n)R⁵)₂, —(CH₂)_(n)NH—COR, —CH(CH₂)_(n)R⁵—(CH₂)_(n)C₃-C₁₀-cycloalkyl, —(CH₂)_(n)—C₃-C_(C) ₁₀-cycloalkyl, C₃-C₁₀-cycloalkyl; C₁-C₆-alkyl, C₃-C₁₀-cycloalkyl, —(CH₂)_(n)—O—(CH₂)_(n)—R⁵, —(CH₂)_(n)—NR³R⁴ that is optionally substituted in one or more places in the same way or differently with hydroxy, C₁-C₆-alkyl or the group —COONH(CH₂)_(n)CH₃ or —NR³R⁴, —CH(C₃H₇)—(CH₂)_(n)—OC(O)—(CH₂)_(n)—CH₃, —(CH₂)_(n)—R⁵, —C(CH₃)₂—(CH₂)_(n)—R⁵, —C(CH₂)_(n)(CH₃)—(CH₂)_(n)R⁵, —C(CH₂)_(n)—(CH₂)_(n)R⁵, —CH(t-butyl)-(CH₂)_(n)—R⁵, —CCH₃(C₃H₇)—(CH₂)_(n)R⁵, —CH(C₃H₇)—(CH₂)_(n)—R⁵, —CH(C₃H₇)—COR⁵, —CH(C₃H₇)—(CH₂)_(n)—OC(O)—NH-Ph, —CH((CH₂)_(n)(C₃H₇))—(CH₂)_(n)R⁵, —CH(C₃H₇)—(CH₂)_(n)—OC(O)—NH-Ph(OR⁵)₃, —NR³R⁴, —NH—(CH₂)_(n)—NR³R⁴, R⁵—(CH₂)_(n)—C*H—CH(R⁵)—(CH₂)_(n)—R⁵, —(CH₂)_(n)—CO—NH—(CH₂)_(n)—CO—R⁵, —OC(O)NH—C₁-C₆-alkyl or —(CH₂)_(n)—CO—NH—(CH₂)_(n)—CH—((CH₂)_(n)R⁵)₂, or for C₃-C₁₀-cycloalkyl, which is substituted with the group

or for the group

X stands for oxygen or for the group —NH—, —N(C₁-C₃-alkyl) or

or R¹ stands for the group

or X and R² together form a group

A and B, in each case independently of one another, stand for hydrogen, hydroxy, C₁-C₃-alkyl, C₁-C₆-alkoxy or for the group —S—CH₃, —SO₂—C₂H₄—OH, —CO—CH₃, —S—CHF₂, —S(CH₂)_(n)CH(OH)CH₂N—R³R⁴, —CH₂PO(OC₂H₅)₂, —S—CF₃, —SO—CH₃, —SO₂CF₃, —SO₂—(CH₂)_(n)—N—R³R⁴, —SO₂—NR³R⁴, —SO₂R⁷, —CH(OH)—CH₃, —COOH, —CH((CH₂)_(n)R⁵)₂, —(CH₂)_(n)R⁵, —COO—C₁-C₆-alkyl, —CONR³R⁴ or for

or A and B together can form a group

or R³ and R⁴, in each case independently of one another, stand for hydrogen, phenyl, benzyloxy, C₁-C₁₂-alkyl, C₁-C₆-alkoxy, C₂-C₄-alkenyloxy, C₃-C₆-cycloalkyl, hydroxy, hydroxy-C₁-C₆-alkyl, dihydroxy-C₁-C₆-alkyl, heteroaryl, heterocyclo-C₃-C₁₀-alkyl, heteroaryl-C₁-C₃-alkyl, C₃-C₆-cycloalkyl-C₁-C₃-alkyl that is optionally substituted with cyano, or for C₁-C₆-alkyl that is optionally substituted in one or more places in the same way or differently with phenyl, pyridyl, phenyloxy, C₃-C₆-cycloalkyl, C₁-C₆-alkyl or C₁-C₆-alkoxy, whereby the phenyl itself can be substituted in one or more places in the same way or differently with halogen, trifluoromethyl, C₁-C₆-alkyl, C₁-C₆-alkoxy or with the group —SO₂NR³R⁴, or for the group —(CH₂)_(n)NR³R⁴, —CNHNH₂ or —NR³R⁴ or for

or which optionally can be substituted with C₁-C₆-alkyl, R⁵ stands for hydroxy, phenyl, C₁-C₆-alkyl, C₃-C₆-cycloalkyl, benzoxy, C₁-C₆-alkylthio or C₁-C₆-alkoxy, R⁶ stands for the group

R⁷ stands for halogen, hydroxy, phenyl, C₁-C₆-alkyl, —(CH₂)_(n)OH, —NR³R⁴ or the group

R⁸, R⁹ and R¹⁰ stand for hydrogen, hydroxy, C₁-C₆-alkyl or for the group —(CH₂)_(n)—COOH, and n stands for 0-6, as well as isomers, diastereomers, enantiomers and salts thereof
 4. Use of the compound of general formula Ia

In which D stands for halogen, and X, R¹, and R² have the meanings that are indicated in general formula (I), as intermediate products for the production of the compound of general formula I.
 5. Use of the compounds of general formula Ia, according to claim 4, in which D stands for chlorine and X, R¹ and R² have the meanings that are indicated in the general formula.
 6. Pharmaceutical agents that comprise a compound of general formula I in which R¹ stands for halogen or C₁-C₃-alkyl X stands for oxygen or —NH, A stands for hydrogen B stands for hydroxy, —CO-alkyl-R⁷, —S—CHF₂, —S—(CH₂)_(n)CH(OH)CH₂N—R³R⁴, —S—CF₃, or —CH—(OH)—CH₃, or A and B, independently of one another, can form a group

R², R³, R⁴, R⁵ and R⁶ have the meanings that are indicated in general formula I, as well as isomers, diastereomers, enantiomers and salts thereof.
 7. Use of the compounds of general formula I, according to claims 1 to 3, for the production of a pharmaceutical agent for treating cancer, auto-immune diseases, chemotherapy agent-induced alopecia and mucositis, cardiovascular diseases, infectious diseases, nephrological diseases, chronic and acute neurodegenerative diseases and viral infections.
 8. Use according to claim 7, wherein cancer is defined as solid tumors and leukemia; auto-immune diseases are defined as psoriasis, alopecia and multiple sclerosis; cardiovascular diseases are defined as stenoses, arterioscleroses and restenoses; infectious diseases are defined as diseases that are caused by unicellular parasites; nephrological diseases are defined as glomerulonephritis; chronic neurodegenerative diseases are defined as Huntington's disease, amyotrophic lateral sclerosis, Parkinson's disease, AIDS dementia and Alzheimer's disease; acute neurodegenerative diseases are defined as ischemias of the brain and neurotraumas; and viral infections are defined as cytomegalic infections, herpes, hepatitis B and C, and HIV diseases.
 9. Pharmaceutical agents that contain at least one compound according to claims 1 to
 3. 10. Pharmaceutical agent according to claim 9 for treating cancer, auto-immune diseases, cardiovascular diseases, infectious diseases, nephrological diseases, neurodegenerative diseases and viral infections.
 11. Compounds according to claims 1 to 3 and pharmaceutical agents according to claims 6 to 7, with suitable formulation substances and vehicles.
 12. Use of the compounds of general formula I and the pharmaceutical agents, according to claims 1 to 3 and 6, as inhibitors of the cyclin-dependent kinases.
 13. Use according to claim 12, wherein the kinase is CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8 or CDK9.
 14. Use of the compounds of general formula I and the pharmaceutical agents, according to claims 1 to 3 and 6, as inhibitors of the glycogen-synthase-kinase (GSK-3β).
 15. Use of the compounds of general formula I, according to claims 1 to 3, in the form of a pharmaceutical preparation for enteral, parenteral and oral administration.
 16. Use of the agent according to claim 6, in the form of a preparation for enteral, parenteral and oral administration. 